Retinal capillary perfusion heterogeneity in diabetic retinopathy detected by optical coherence tomography angiography.

BACKGROUND: Diabetic retinopathy (DR) is a leading cause of blindness and involves retinal capillary damage, microaneurysms, and altered blood flow regulation. Optical coherence tomography angiography (OCTA) is a non-invasive way of visualizing retinal vasculature but has not been used extensively to study blood flow heterogeneity. The purpose of this study is to detect and quantify blood flow heterogeneity utilizing en-face swept source OCTA in patients with DR. METHODS: This is a prospective clinical study which examined patients with either type 1 or 2 diabetes mellitus. Each included eye was graded clinically as no DR, mild DR, or moderate-severe DR. Ten consecutive en face 6 × 6 mm foveal SS-OCTA images were obtained from each eye using a PLEX Elite 9000 (Zeiss Meditec, Dublin, CA). Built-in fixation-tracking, follow-up functions were utilized to reduce motion artifacts and ensure same location imaging in sequential frames. Images of the superficial and deep vascular complexes (SVC and DVC) were arranged in temporal stacks of 10 and registered to a reference frame for segmentation using a deep neural network. The vessel segmentation was then masked onto each stack to calculate the pixel intensity coefficient of variance (PICoV) and map the spatiotemporal perfusion heterogeneity of each stack. RESULTS: Twenty-nine eyes were included: 7 controls, 7 diabetics with no DR, 8 mild DR, and 7 moderate-severe DR. The PICoV correlated significantly and positively with DR severity. In patients with DR, the perfusion heterogeneity was higher in the temporal half of the macula, particularly in areas of capillary dropout. PICoV also correlates as expected with the established OCTA metrics of perfusion density and vessel density. CONCLUSION: PICoV is a novel way to analyze OCTA imaging and quantify perfusion heterogeneity. Retinal capillary perfusion heterogeneity in both the SVC and DVC increased with DR severity. This may be related to the loss of retinal capillary perfusion autoregulation in diabetic retinopathy.

Posture-Induced Changes in Intraocular, Orbital, Cranial, Jugular Vein, and Arterial Pressures in a Porcine Model.

Purpose: The purpose of this study was to determine posture-induced changes in arterial blood pressure (ABP), intraocular pressure (IOP), orbital pressure (Porb), intracranial pressure (ICP), and jugular vein pressure (JVP) at various tilt angles in an in vivo pig. Methods: Anesthetized and ventilated pigs (n = 8) were placed prone on a tiltable operating table. ABP, IOP, Porb, ICP, and JVP were monitored while the table was tilted at various angles between 15 degrees head up tilt (HUT) and 25 degrees head down tilt (HDT) either in stepwise changes (5 degrees per step) or continuously. The mean pressure was calculated from digitized pressure waveforms from each compartment. For stepwise changes in tilt angle the pressures were plotted as a function of tilt angle. For continuous tilt changes, the pressures were plotted as a function of time. Results: In the case of stepwise changes, ABP remained relatively stable whilst IOP, Porb, ICP, and JVP demonstrated significant differences between most angles (typically P < 0.0001). The difference was greatest for IOP (P < 0.0001) where the average IOP increased from 13.1 ± 1.23 mm Hg at 15 degrees HUT to 46.3 ± 2.03 mm Hg at 25 degrees HDT. The relationship between pressure and tilt angle was almost linear for ICP and JVP, and sigmoidal for IOP and Porb. Interestingly, the effect of changes in tilt angle occurred very rapidly, within a few seconds. Conclusions: Our results in a pig model demonstrate that changes in posture (tilt angle) induce rapid changes in IOP, Porb, ICP, and JVP, with IOP affected most severely.

Quantitative study of spatial and temporal variation in retinal capillary network perfusion in rat eye by in vivo confocal imaging.

Microvascular dysfunction is the underlying pathological process in many systemic diseases. However, investigation into its pathogenesis is impeded by the accessibility and complexity of the microvasculature within different organs, particularly for the central nervous system. The retina as an extension of the cerebrum provides a glimpse into the brain through which the microvasculature can be observed. Two major questions remain unanswered: How do the microvessels regulate spatial and temporal delivery to satisfy the varying cellular demands, and how can we quantify blood perfusion in the 3D capillary network? Here, quantitative measurements of red blood cell (RBC) speed in each vessel in the field were made in the in vivo rat retinal capillary network using an ultrafast confocal technique with fluorescently labelled RBCs. Retinal RBC speed and number were found to vary remarkably between microvessels ranging from 215 to 6641 microns per second with significant variations spatially and temporally. Overall, the RBC speed was significantly faster in the microvessels in the superficial retina than in the deep retina (estimated marginal means of 2405 ± 238.2 µm/s, 1641 ± 173.0 µm/s respectively). These observations point to a highly dynamic nature of microvasculature that is specific to its immediate cellular environment and is constantly changing.

Variability in Capillary Perfusion Is Increased in Regions of Retinal Ischemia Due to Branch Retinal Vein Occlusion.

Purpose: To investigate alterations in macular perfusion variability due to branch retinal vein occlusion (BRVO) using a novel approach based on optical coherence tomography angiography (OCTA) coefficient of variation (CoV) analysis. Methods: Thirteen eyes of 13 patients with macular ischemia due to BRVO were studied. Multiple consecutive en face OCTA images were acquired. Bias field correction, spatial alignment, and normalization of intensities across the images were performed followed by pixelwise computation of standard deviation divided by the mean to generate a CoV map. Region of interest-based CoV values, derived from this map, for arterioles, venules, and the microvasculature were compared between regions with macular ischemia and control areas of the same eye. Control areas were regions of the same macula that were not affected by the BRVO and had normal retinal vascular structure as seen on multimodal imaging and normal retinal vascular density measurements as quantified using OCTA. Results: CoV increased by a mean value of 17.6% within the microvasculature of ischemic regions compared to the control microvasculature (P < 0.0001). CoV measurements of microvasculature were consistently greater in the ischemic area of all 13 eyes compared to control. There were no differences in CoV measurements between ischemic and control areas for arterioles (P = 0.13) and venules (P = 1.0). Conclusions: Greater variability in microvasculature perfusion occurs at sites of macular ischemia due to BRVO. We report a novel way for quantifying macular perfusion variability using OCTA. This technique may have applicability for studying the pathophysiology of other retinal vascular diseases.

An assessment of microvascular hemodynamics in human macula.

An adequate blood supply to meet the energy demands is essential for any tissue, particularly for high energy demand tissues such as the retina. A critical question is: How is the dynamic match between neuronal demands and blood supply achieved? We present a quantitative assessment of temporal and spatial variations in perfusion in the macular capillary network in 10 healthy human subjects using a non-invasive and label-free imaging technique. The assessment is based on the calculation of the coefficient of variation (CoV) of the perfusion signal from arterioles, venules and capillaries from a sequence of optical coherence tomography angiography images centred on the fovea. Significant heterogeneity of the spatial and temporal variation was found within arterioles, venules and capillary networks. The CoV values of the capillaries and smallest vessels were significantly higher than that in the larger vessels. Our results demonstrate the presence of significant heterogeneity of spatial and temporal variation within each element of the macular microvasculature, particularly in the capillaries and finer vessels. Our findings suggest that the dynamic match between neuronal demands and blood supply is achieved by frequent alteration of local blood flow evidenced by capillary perfusion variations both spatially and temporally in the macular region.

Empirical retinal venous pulse wave velocity using modified photoplethysmography.

OBJECTIVE: Using the novel imaging method of high-speed modified photoplethysmography we measured the retinal venous pulse wave velocity in a single case. RESULTS: A healthy 30-year-old subject underwent high-speed modified photoplethysmography (120 frames per second) with simultaneous ophthalmodynamometry at 26 Meditron units. A video of the optic nerve was analyzed using custom software. A harmonic regression model was fitted to each pixel in the time series and used to quantify the retinal vascular pulse wave parameters. Retinal venous pulsation at the optic disc was observed as a complex dynamic wall motion, whereas contraction commenced at a point in the vein at the center of the optic disc, and progressed centrifugally. The empirically estimated retinal venous pulse wave velocity at this segment was approximately 22.24694 mm/s. This measurement provides an estimate for future studies in the field.

Endothelial contraction of retinal veins.

We have previously reported that porcine retinal veins can be contracted by vasoactive factors such as endothelin-1, but it is still unknown which cells play the major role in such contraction responses. This study seeks to confirm whether retinal vein endothelial cells play a significant role in the endothelin-1 induced contraction of porcine retinal veins. This is a novel study which provides confirmation of the endothelial cells' ability to contract retinal veins using a live vessel preparation. Retinal veins were isolated from porcine retina and cannulated for perfusion. The vessels were exposed to extraluminal delivery of endothelin-1 (10-8 M) and change in vessel diameter recorded automatically every 2 s. A phase contrast objective lens was also used to capture images of the endothelial cell morphometries. The length, width, area, and perimeter were assessed. In addition, vein histology and immuno-labeling for contractile proteins was performed. With 10-8 M endothelin-1 contractions to 63.6% of baseline were seen. The polygonal shape of the endothelial cells under normal tone became spindle-like after contraction. The area, width, perimeter and length were significantly reduced by 54.8%, 48.1%, 28.5% and 10.5% respectively. Three contractile proteins, myosin, calponin and alpha-SMA were found in retinal vein endothelial cells. Retinal vein endothelial cells contain contractile proteins and can be contracted by endothelin-1 administration. Such contractile capability may be important in regulating retinal perfusion but could also be a factor in the pathogenesis of retinal vascular diseases such as retinal vein occlusion. As far as we are aware, this is the first study on living isolated veins to confirm that endothelial cells contribute to the endothelin-1 induced contraction.

MSGANet-RAV: A multiscale guided attention network for artery-vein segmentation and classification from optic disc and retinal images.

BACKGROUND: Retinal and optic disc images are used to assess changes in the retinal vasculature. These can be changes associated with diseases such as diabetic retinopathy and glaucoma or induced using ophthalmodynamometry to measure arterial and venous pressure. Key steps toward automating the assessment of these changes are the segmentation and classification of the veins and arteries. However, such segmentation and classification are still required to be manually labelled by experts. Such automated labelling is challenging because of the complex morphology, anatomical variations, alterations due to disease and scarcity of labelled data for algorithm development. We present a deep machine learning solution called the multiscale guided attention network for retinal artery and vein segmentation and classification (MSGANet-RAV). METHODS: MSGANet-RAV was developed and tested on 383 colour clinical optic disc images from LEI-CENTRAL, constructed in-house and 40 colour fundus images from the AV-DRIVE public dataset. The datasets have a mean optic disc occupancy per image of 60.6% and 2.18%, respectively. MSGANet-RAV is a U-shaped encoder-decoder network, where the encoder extracts multiscale features, and the decoder includes a sequence of self-attention modules. The self-attention modules explore, guide and incorporate vessel-specific structural and contextual feature information to segment and classify central optic disc and retinal vessel pixels. RESULTS: MSGANet-RAV achieved a pixel classification accuracy of 93.15%, sensitivity of 92.19%, and specificity of 94.13% on LEI-CENTRAL, outperforming several reference models. It similarly performed highly on AV-DRIVE with an accuracy, sensitivity and specificity of 95.48%, 93.59% and 97.27%, respectively. CONCLUSION: The results show the efficacy of MSGANet-RAV for identifying central optic disc and retinal arteries and veins. The method can be used in automated systems designed to assess vascular changes in retinal and optic disc images quantitatively.

Quantifying variation in female internal genitalia: no evidence for plasticity in response to sexual conflict risk in a seed beetle.

Sexually antagonistic coevolution can drive the evolution of male traits that harm females, and female resistance to those traits. While males have been found to vary their harmfulness to females in response to social cues, plasticity in female resistance traits remains to be examined. Here, we ask whether female seed beetles Callosobruchus maculatus are capable of adjusting their resistance to male harm in response to the social environment. Among seed beetles, male genital spines harm females during copulation and females might resist male harm via thickening of the reproductive tract walls. We develop a novel micro computed tomography imaging technique to quantify female reproductive tract thickness in three-dimensional space, and compared the reproductive tracts of females from populations that had evolved under high and low levels of sexual conflict, and for females reared under a social environment that predicted either high or low levels of sexual conflict. We find little evidence to suggest that females can adjust the thickness of their reproductive tracts in response to the social environment. Neither did evolutionary history affect reproductive tract thickness. Nevertheless, our novel methodology was capable of quantifying fine-scale differences in the internal reproductive tracts of individual females, and will allow future investigations into the internal organs of insects and other animals.

Use of the Retinal Vascular Histology to Validate an Optical Coherence Tomography Angiography Technique.

Purpose: To determine the fidelity of optical coherence tomography angiography (OCTA) techniques by direct comparison of the retinal capillary network images obtained from the same region as imaged by OCTA and high-resolution confocal microscope. Method: Ten porcine eyes were perfused with red blood cells for OCTA image acquisition from the area centralis and then perfusion-fixed, and the vessels were labeled for confocal imaging. Two approaches involving post-processing of two-dimensional projection images and vessel tracking on three dimensional image stacks were used to obtain quantitative measurements. Data collected include vessel density, length of visible vessel track, count of visible branch points, vessel track depth, vessel diameter, angle of vessel descent, and angle of dive for comparison and analysis. Results: Comparing vascular images acquired from OCTA and confocal microscopy, we found (1) a good representation of the larger caliber retinal vessels, (2) an underrepresentation of retinal microvessels smaller than 10 µm and branch points in all four retinal vascular plexuses, particularly the intermediate capillary plexus, (3) reduced visibility associated with an increase in the angle of descent, (4) a tendency to loss visibility of vessel track at a branch point or during a sharp dive, and (5) a reduction in visibility with increase in retinal depth on OCTA images. Conclusions: Current OCTA techniques can visualize the retinal capillary network, but some types of capillaries cannot be detected by OCTA, particularly in the middle to deeper layers. Translational Relevance: The information indicates the limitation in clinical use and scopes for improvement in the current OCTA technologies.

Multimodal Imaging and Analysis of the Neuroanatomical Organization of the Primary Olfactory Inputs in the Brownbanded Bamboo Shark, Chiloscyllium punctatum.

There is currently a limited understanding of the morphological and functional organization of the olfactory system in cartilaginous fishes, particularly when compared to bony fishes and terrestrial vertebrates. In this fish group, there is a clear paucity of information on the characterization, density, and distribution of olfactory receptor neurons (ORNs) within the sensory olfactory epithelium lining the paired olfactory rosettes, and their functional implications with respect to the hydrodynamics of incurrent water flow into the nares. This imaging study examines the brownbanded bamboo shark Chiloscyllium punctatum (Elasmobranchii) and combines immunohistochemical labeling using antisera raised against five G-protein α-subunits (Gαs/olf, Gαq/ 11 / 14, Gαi- 1 / 2 / 3, Gαi- 3, Gα o ) with light and electron microscopy, to characterize the morphological ORN types present. Three main ORNs ("long", "microvillous" and "crypt-like") are confirmed and up to three additional microvilli-bearing types are also described; "Kappe-like" (potential or homologous "Kappe" as in teleosts), "pear-shaped" and "teardrop-shaped" cells. These morphotypes will need to be confirmed molecularly in the future. Using X-ray diffusible iodine-based contrast-enhanced computed tomography (diceCT), high-resolution scans of the olfactory rosettes, olfactory bulbs (OBs), peduncles, and telencephalon reveal a lateral segregation of primary olfactory inputs within the OBs, with distinct medial and lateral clusters of glomeruli, suggesting a potential somatotopic organization. However, most ORN morphotypes are found to be ubiquitously distributed within the medial and lateral regions of the olfactory rosette, with at least three microvilli-bearing ORNs labeled with anti-Gα o found in significantly higher densities in lateral lamellae [in lateral lamellae] and on the anterior portion of lamellae (facing the olfactory cavity). These microvilli-bearing ORN morphotypes (microvillous, "Kappe-like," "pear-shaped," and "teardrop-shaped") are the most abundant across the olfactory rosette of this species, while ciliated ORNs are less common and crypt cells are rare. Spatial simulations of the fluid dynamics of the incurrent water flow into the nares and within the olfactory cavities indicate that the high densities of microvilli-bearing ORNs located within the lateral region of the rosette are important for sampling incoming odorants during swimming and may determine subsequent tracking behavior.

diceCT: A Valuable Technique to Study the Nervous System of Fish.

Contrast-enhanced X-ray imaging provides a non-destructive and flexible approach to optimizing contrast in soft tissues, especially when incorporated with Lugol's solution (aqueous I2KI), a technique currently referred to as diffusible iodine-based contrast-enhanced computed tomography (diceCT). This stain exhibits high rates of penetration and results in excellent contrast between and within soft tissues, including the central nervous system. Here, we present a staining method for optimizing contrast in the brain of a cartilaginous fish, the brownbanded bamboo shark, Chiloscyllium punctatum, and a bony fish, the common goldfish, Carassius auratus, using diceCT. The aim of this optimization procedure is to provide suitable contrast between neural tissue and background tissue(s) of the head, thereby facilitating digital segmentation and volumetric analysis of the central nervous system. Both species were scanned before staining and were rescanned at time (T) intervals, either every 48 h (C. punctatum) or every 24 h (C. auratus), to assess stain penetration and contrast enhancement. To compare stain intensities, raw X-ray CT data were reconstructed using air and water calibration phantoms that were scanned under identical conditions to the samples. Optimal contrast across the brain was achieved at T = 240 h for C. punctatum and T = 96 h for C. auratus Higher resolution scans of the whole brain were obtained at the two optimized staining times for all the corresponding specimens. The use of diceCT provides a new and valuable tool for visualizing differences in the anatomic organization of both the central and peripheral nervous systems of fish.

Ex Vivo MRI Analytical Methods and Brain Pathology in Preterm Lambs Treated with Postnatal Dexamethasone †.

Postnatal glucocorticoids such as dexamethasone are effective in promoting lung development in preterm infants, but are prescribed cautiously due to concerns of neurological harm. We developed an analysis pipeline for post-mortem magnetic resonance imaging (MRI) to assess brain development and hence the neurological safety profile of postnatal dexamethasone in preterm lambs. Lambs were delivered via caesarean section at 129 days' (d) gestation (full term ≈ 150 d) with saline-vehicle control (Saline, n = 9), low-dose tapered dexamethasone (cumulative dose = 0.75 mg/kg, n = 8), or high-dose tapered dexamethasone (cumulative dose = 2.67 mg/kg, n = 8), for seven days. Naïve fetal lambs (136 d gestation) were used as end-point maturation controls. The left-brain hemispheres were immersion-fixed in 10 % formalin (24 h), followed by paraformaldehyde (>6 months). Image sequences were empirically optimized for T1- and T2-weighted MRI and analysed using accessible methods. Spontaneous lesions detected in the white matter of the frontal cortex, temporo-parietal cortex, occipital lobe, and deep to the parahippocampal gyrus were confirmed with histology. Neither postnatal dexamethasone treatment nor gestation showed any associations with lesion incidence, frontal cortex (total, white, or grey matter) or hippocampal volume (all p > 0.05). Postnatal dexamethasone did not appear to adversely affect neurodevelopment. Our post-mortem MRI analysis pipeline is suitable for other animal models of brain development.

Quantitative characterization of rodent feto-placental vasculature morphology in micro-computed tomography images.

BACKGROUND AND OBJECTIVE: Optimal development of placental vasculature is critical for fetal growth and health outcomes. Many studies characterizing the vascular structure of the fetal side of the placenta have utilized a range of two-dimensional and three-dimensional (3D) imaging techniques including X-ray micro-computed tomography (micro-CT) following perfusion of the vasculature with a radio-opaque compound. The CT approach has been used to study feto-placental vasculature in rodents and humans. Its inherent advantage is that it reveals the 3D structure in high resolution without destroying the sample. This permits both multiple scanning of the sample and follow-up histological investigations in the same sample. Nevertheless, the applicability of the approach is hampered both by the challenging segmentation of the vasculature and a lack of straightforward methodology to quantitate the feto-placental vascular network. This paper addresses these challenges. METHODS: An end-to-end methodology is presented for automatically segmenting the vasculature; obtaining a Strahler-ordered rooted-tree representation and extracting quantitative features from its nodes, segments and branches (including volume, length, tortuosity and branching angles). The methodology is demonstrated for rat and mouse placentas at the end of gestation (day 22 and day 18, respectively), perfused with Microfil® and imaged using two different micro-CT scanners. RESULTS: The 3D visualizations of the resulting vascular trees clearly demonstrate differences between the branching complexity, tree span and tree depth of the mouse and rat placentas. The quantitative characterizations of these trees include not only the fundamental features that have been utilized in other studies of feto-placental vasculature but also several additional features. Boxplots of several of these-tortuosity, number of side branches, number of offspring per branch and branch volume-computed at each Strahler order are presented and interpreted. Differences and similarities between the mouse and rat casts are readily detected. CONCLUSION: The proposed end-to-end methodology, and the implementation presented using a combination of Amira and Matlab, offers researchers in the field of placental vasculature characterization a straightforward and objective approach for quantifying micro-CT vascular datasets.

Retinal capillary perfusion: Spatial and temporal heterogeneity.

The central role of the cardiovascular system is to maintain adequate capillary perfusion. The spatially and temporally heterogeneous nature of capillary perfusion has been reported in some organs. However, such heterogeneous perfusion properties have not been sufficiently explored in the retina. Arguably, spatial and temporal heterogeneity of capillary perfusion could be more predominant in the retina than that in other organs. This is because the retina is one of the highest metabolic demand neural tissues yet it has a limited blood supply due to optical requirements. In addition, the unique heterogeneous distribution of retinal neural cells within different layers and regions, and the significant heterogeneity of intraretinal oxygen distribution and consumption add to the complexity. Retinal blood flow distribution must match consumption of nutrients such as oxygen and glucose within the retina at the cellular level in order to effectively maintain cell survival and function. Sophisticated local blood flow control in the microcirculation is likely required to control the retinal capillary perfusion to supply local retinal tissue and accommodate temporal and spatial variations in metabolic supply and demand. The authors would like to update the knowledge of the retinal microvessel and capillary network and retinal oxidative metabolism from their own studies and the work of others. The coupling between blood supply and energy demands in the retina is particularly interesting. We will mostly describe information regarding the retinal microvessel network and retinal oxidative metabolism relevant to the spatial and temporal heterogeneity of capillary perfusion. We believe that there is significant and necessary spatial and temporal heterogeneity and active regulation of retinal blood flow in the retina, particularly in the macular region. Recently, retinal optical coherence tomography angiography (OCTA) has been widely used in ophthalmology, both experimentally and clinically. OCTA could be a valuable tool for examining retinal microvessel and capillary network structurally and has potential for determining retinal capillary perfusion and its control. We have demonstrated spatial and temporal heterogeneity of capillary perfusion in the retina both experimentally and clinically. We have also found close relationships between the smallest arterioles and capillaries within paired arterioles and venules and determined the distribution of smooth muscle cell contraction proteins in these vessels. Spatial and temporal heterogeneity of retinal capillary perfusion could be a useful parameter to determine retinal microvessel regulatory capability as an early assay for retinal vascular diseases. This topic will be of great interest, not only for the eye but also other organs. The retina could be the best model for such investigations. Unlike cerebral vessels, retinal vessels can be seen even at the capillary level. The purpose of this manuscript is to share our current understanding with the readers and encourage more researchers and clinicians to investigate this field. We begin by reviewing the general principles of microcirculation properties and the spatial and temporal heterogeneity of the capillary perfusion in other organs, before considering the special requirements of the retina. The local heterogeneity of oxygen supply and demand in the retina and the need to have a limited and well-regulated retinal circulation to preserve the transparency of the retina is discussed. We then consider how such a delicate balance of metabolic supply and consumption is achieved. Finally we discuss how new imaging methodologies such as optical coherence tomography angiography may be able to detect the presence of spatial and temporal heterogeneity of capillary perfusion in a clinical setting. We also provide some new information of the control role of very small arterioles in the modulation of retinal capillary perfusion which could be an interesting topic for further investigation.

K-Optimal Gradient Encoding Scheme for Fourth-Order Tensor-Based Diffusion Profile Imaging.

The design of an optimal gradient encoding scheme (GES) is a fundamental problem in diffusion MRI. It is well studied for the case of second-order tensor imaging (Gaussian diffusion). However, it has not been investigated for the wide range of non-Gaussian diffusion models. The optimal GES is the one that minimizes the variance of the estimated parameters. Such a GES can be realized by minimizing the condition number of the design matrix (K-optimal design). In this paper, we propose a new approach to solve the K-optimal GES design problem for fourth-order tensor-based diffusion profile imaging. The problem is a nonconvex experiment design problem. Using convex relaxation, we reformulate it as a tractable semidefinite programming problem. Solving this problem leads to several theoretical properties of K-optimal design: (i) the odd moments of the K-optimal design must be zero; (ii) the even moments of the K-optimal design are proportional to the total number of measurements; (iii) the K-optimal design is not unique, in general; and (iv) the proposed method can be used to compute the K-optimal design for an arbitrary number of measurements. Our Monte Carlo simulations support the theoretical results and show that, in comparison with existing designs, the K-optimal design leads to the minimum signal deviation.

Optimal Experiment Design for Monoexponential Model Fitting: Application to Apparent Diffusion Coefficient Imaging.

The monoexponential model is widely used in quantitative biomedical imaging. Notable applications include apparent diffusion coefficient (ADC) imaging and pharmacokinetics. The application of ADC imaging to the detection of malignant tissue has in turn prompted several studies concerning optimal experiment design for monoexponential model fitting. In this paper, we propose a new experiment design method that is based on minimizing the determinant of the covariance matrix of the estimated parameters (D-optimal design). In contrast to previous methods, D-optimal design is independent of the imaged quantities. Applying this method to ADC imaging, we demonstrate its steady performance for the whole range of input variables (imaged parameters, number of measurements, and range of b-values). Using Monte Carlo simulations we show that the D-optimal design outperforms existing experiment design methods in terms of accuracy and precision of the estimated parameters.

Unsupervised Segmentation of Head Tissues from Multi-modal MR Images for EEG Source Localization.

In this paper, we present and evaluate an automatic unsupervised segmentation method, hierarchical segmentation approach (HSA)-Bayesian-based adaptive mean shift (BAMS), for use in the construction of a patient-specific head conductivity model for electroencephalography (EEG) source localization. It is based on a HSA and BAMS for segmenting the tissues from multi-modal magnetic resonance (MR) head images. The evaluation of the proposed method was done both directly in terms of segmentation accuracy and indirectly in terms of source localization accuracy. The direct evaluation was performed relative to a commonly used reference method brain extraction tool (BET)-FMRIB's automated segmentation tool (FAST) and four variants of the HSA using both synthetic data and real data from ten subjects. The synthetic data includes multiple realizations of four different noise levels and several realizations of typical noise with a 20% bias field level. The Dice index and Hausdorff distance were used to measure the segmentation accuracy. The indirect evaluation was performed relative to the reference method BET-FAST using synthetic two-dimensional (2D) multimodal magnetic resonance (MR) data with 3% noise and synthetic EEG (generated for a prescribed source). The source localization accuracy was determined in terms of localization error and relative error of potential. The experimental results demonstrate the efficacy of HSA-BAMS, its robustness to noise and the bias field, and that it provides better segmentation accuracy than the reference method and variants of the HSA. They also show that it leads to a more accurate localization accuracy than the commonly used reference method and suggest that it has potential as a surrogate for expert manual segmentation for the EEG source localization problem.

Fully automatic lesion segmentation in breast MRI using mean-shift and graph-cuts on a region adjacency graph.

PURPOSE: To present and evaluate a fully automatic method for segmentation (i.e., detection and delineation) of suspicious tissue in breast MRI. MATERIALS AND METHODS: The method, based on mean-shift clustering and graph-cuts on a region adjacency graph, was developed and its parameters tuned using multimodal (T1, T2, DCE-MRI) clinical breast MRI data from 35 subjects (training data). It was then tested using two data sets. Test set 1 comprises data for 85 subjects (93 lesions) acquired using the same protocol and scanner system used to acquire the training data. Test set 2 comprises data for eight subjects (nine lesions) acquired using a similar protocol but a different vendor's scanner system. Each lesion was manually delineated in three-dimensions by an experienced breast radiographer to establish segmentation ground truth. The regions of interest identified by the method were compared with the ground truth and the detection and delineation accuracies quantitatively evaluated. RESULTS: One hundred percent of the lesions were detected with a mean of 4.5 ± 1.2 false positives per subject. This false-positive rate is nearly 50% better than previously reported for a fully automatic breast lesion detection system. The median Dice coefficient for Test set 1 was 0.76 (interquartile range, 0.17), and 0.75 (interquartile range, 0.16) for Test set 2. CONCLUSION: The results demonstrate the efficacy and accuracy of the proposed method as well as its potential for direct application across different MRI systems. It is (to the authors' knowledge) the first fully automatic method for breast lesion detection and delineation in breast MRI.

On high order tensor-based diffusivity profile estimation.

Diffusion weighted magnetic resonance imaging (dMRI) is used to measure, in vivo, the self-diffusion of water molecules in biological tissues. High order tensors (HOTs) are used to model the apparent diffusion coefficient (ADC) profile at each voxel from the dMRI data. In this paper we propose: (i) A new method for estimating HOTs from dMRI data based on weighted least squares (WLS) optimization; and (ii) A new expression for computing the fractional anisotropy from a HOT that does not suffer from singularities and spurious zeros. We also present an empirical evaluation of the proposed method relative to the two existing methods based on both synthetic and real human brain dMRI data. The results show that the proposed method yields more accurate estimation than the competing methods.