Publications by authors named "Anil A Bharath"

16 Publications

  • Page 1 of 1

Dynamic changes in cell size and corresponding cell fate after optic nerve injury.

Sci Rep 2020 12 10;10(1):21683. Epub 2020 Dec 10.

Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.

Identifying disease-specific patterns of retinal cell loss in pathological conditions has been highlighted by the emergence of techniques such as Detection of Apoptotic Retinal Cells and Adaptive Optics confocal Scanning Laser Ophthalmoscopy which have enabled single-cell visualisation in vivo. Cell size has previously been used to stratify Retinal Ganglion Cell (RGC) populations in histological samples of optic neuropathies, and early work in this field suggested that larger RGCs are more susceptible to early loss than smaller RGCs. More recently, however, it has been proposed that RGC soma and axon size may be dynamic and change in response to injury. To address this unresolved controversy, we applied recent advances in maximising information extraction from RGC populations in retinal whole mounts to evaluate the changes in RGC size distribution over time, using three well-established rodent models of optic nerve injury. In contrast to previous studies based on sampling approaches, we examined the whole Brn3a-positive RGC population at multiple time points over the natural history of these models. The morphology of over 4 million RGCs was thus assessed to glean novel insights from this dataset. RGC subpopulations were found to both increase and decrease in size over time, supporting the notion that RGC cell size is dynamic in response to injury. However, this study presents compelling evidence that smaller RGCs are lost more rapidly than larger RGCs despite the dynamism. Finally, using a bootstrap approach, the data strongly suggests that disease-associated changes in RGC spatial distribution and morphology could have potential as novel diagnostic indicators.
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http://dx.doi.org/10.1038/s41598-020-77760-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730151PMC
December 2020

A Semi-Automatic Method To Segment The Left Atrium in MR Volumes With Varying Slice Numbers.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:1198-1202

Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with dramatic increases in mortality and morbidity. Atrial cine MR images are increasingly used in the management of this condition, but there are few specific tools to aid in the segmentation of such data. Some characteristics of atrial cine MR (thick slices, variable number of slices in a volume) preclude the direct use of traditional segmentation tools. When combined with scarcity of labelled data and similarity of the intensity and texture of the left atrium (LA) to other cardiac structures, the segmentation of the LA in CINE MRI becomes a difficult task. To deal with these challenges, we propose a semi-automatic method to segment the left atrium (LA) in MR images, which requires an initial user click per volume. The manually given location information is used to generate a chamber location map to roughly locate the LA, which is then used as an input to a deep network with slightly over 0.5 million parameters. A tracking method is introduced to pass the location information across a volume and to remove unwanted structures in segmentation maps. According to the results of our experiments conducted in an in-house MRI dataset, the proposed method outperforms the U-Net [1] with a margin of 20 mm on Hausdorff distance and 0.17 on Dice score, with limited manual interaction.
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http://dx.doi.org/10.1109/EMBC44109.2020.9175749DOI Listing
July 2020

Strain maps of the left atrium imaged with a novel high-resolution CINE MRI protocol.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:1178-1181

To date, regional atrial strains have not been imaged in vivo, despite their potential to provide useful clinical information. To address this gap, we present a novel CINE MRI protocol capable of imaging the entire left atrium at an isotropic 2-mm resolution in one single breath-hold. As proof of principle, we acquired data in 10 healthy volunteers and 2 cardiovascular patients using this technique. We also demonstrated how regional atrial strains can be estimated from this data following a manual segmentation of the left atrium using automatic image tracking techniques. The estimated principal strains vary smoothly across the left atrium and have a similar magnitude to estimates reported in the literature.
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http://dx.doi.org/10.1109/EMBC44109.2020.9175383DOI Listing
July 2020

Development of a pro-arrhythmic ex vivo intact human and porcine model: cardiac electrophysiological changes associated with cellular uncoupling.

Pflugers Arch 2020 10 1;472(10):1435-1446. Epub 2020 Sep 1.

Faculty of Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.

We describe a human and large animal Langendorff experimental apparatus for live electrophysiological studies and measure the electrophysiological changes due to gap junction uncoupling in human and porcine hearts. The resultant ex vivo intact human and porcine model can bridge the translational gap between smaller simple laboratory models and clinical research. In particular, electrophysiological models would benefit from the greater myocardial mass of a large heart due to its effects on far-field signal, electrode contact issues and motion artefacts, consequently more closely mimicking the clinical setting. Porcine (n = 9) and human (n = 4) donor hearts were perfused on a custom-designed Langendorff apparatus. Epicardial electrograms were collected at 16 sites across the left atrium and left ventricle. A total of 1 mM of carbenoxolone was administered at 5 ml/min to induce cellular uncoupling, and then recordings were repeated at the same sites. Changes in electrogram characteristics were analysed. We demonstrate the viability of a controlled ex vivo model of intact porcine and human hearts for electrophysiology with pharmacological modulation. Carbenoxolone reduces cellular coupling and changes contact electrogram features. The time from stimulus artefact to (-dV/dt) increased between baseline and carbenoxolone (47.9 ± 4.1-67.2 ± 2.7 ms) indicating conduction slowing. The features with the largest percentage change between baseline and carbenoxolone were fractionation + 185.3%, endpoint amplitude - 106.9%, S-endpoint gradient + 54.9%, S point - 39.4%, RS ratio + 38.6% and (-dV/dt) - 20.9%. The physiological relevance of this methodological tool is that it provides a model to further investigate pharmacologically induced pro-arrhythmic substrates.
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http://dx.doi.org/10.1007/s00424-020-02446-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476990PMC
October 2020

Rethinking multiscale cardiac electrophysiology with machine learning and predictive modelling.

Comput Biol Med 2019 01 18;104:339-351. Epub 2018 Oct 18.

ElectroCardioMaths Group, Imperial College Centre for Cardiac Engineering, Imperial College London, London, UK; National Heart and Lung Institute, Imperial College London, South Kensington Campus, London, UK.

We review some of the latest approaches to analysing cardiac electrophysiology data using machine learning and predictive modelling. Cardiac arrhythmias, particularly atrial fibrillation, are a major global healthcare challenge. Treatment is often through catheter ablation, which involves the targeted localised destruction of regions of the myocardium responsible for initiating or perpetuating the arrhythmia. Ablation targets are either anatomically defined, or identified based on their functional properties as determined through the analysis of contact intracardiac electrograms acquired with increasing spatial density by modern electroanatomic mapping systems. While numerous quantitative approaches have been investigated over the past decades for identifying these critical curative sites, few have provided a reliable and reproducible advance in success rates. Machine learning techniques, including recent deep-learning approaches, offer a potential route to gaining new insight from this wealth of highly complex spatio-temporal information that existing methods struggle to analyse. Coupled with predictive modelling, these techniques offer exciting opportunities to advance the field and produce more accurate diagnoses and robust personalised treatment. We outline some of these methods and illustrate their use in making predictions from the contact electrogram and augmenting predictive modelling tools, both by more rapidly predicting future states of the system and by inferring the parameters of these models from experimental observations.
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http://dx.doi.org/10.1016/j.compbiomed.2018.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334203PMC
January 2019

Targeted Cancer Therapy: Correlative Light-Electron Microscopy Shows RGD-Targeted ZnO Nanoparticles Dissolve in the Intracellular Environment of Triple Negative Breast Cancer Cells and Cause Apoptosis with Intratumor Heterogeneity (Adv. Healthcare Mater. 11/2016).

Adv Healthc Mater 2016 Jun;5(11):1248

Department of Materials, Imperial College London, Royal School of Mines, Exhibition Road, London, SW7 2AZ, UK.

On page 1310 J. S. Merzaban, A. E. Porter, and co-workers present fluorescently labeled RGD-targeted ZnO nanoparticles (NPs; green) for the targeted delivery of cytotoxic ZnO to integrin αvβ3 receptors expressed on triple negative breast cancer cells. Correlative light-electron microscopy shows that NPs dissolve into ionic Zn(2+) (blue) upon uptake and cause apoptosis (red) with intra-tumor heterogeneity, thereby providing a possible strategy for targeted breast cancer therapy. Cover design by Ivan Gromicho.
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http://dx.doi.org/10.1002/adhm.201670053DOI Listing
June 2016

Correlative Light-Electron Microscopy Shows RGD-Targeted ZnO Nanoparticles Dissolve in the Intracellular Environment of Triple Negative Breast Cancer Cells and Cause Apoptosis with Intratumor Heterogeneity.

Adv Healthc Mater 2016 06 25;5(11):1310-25. Epub 2016 Apr 25.

Department of Materials, Imperial College London, Royal School of Mines, Exhibition Road, London, SW7 2AZ, UK.

ZnO nanoparticles (NPs) are reported to show a high degree of cancer cell selectivity with potential use in cancer imaging and therapy. Questions remain about the mode by which the ZnO NPs cause cell death, whether they exert an intra- or extracellular effect, and the resistance among different cancer cell types to ZnO NP exposure. The present study quantifies the variability between the cellular toxicity, dynamics of cellular uptake, and dissolution of bare and RGD (Arg-Gly-Asp)-targeted ZnO NPs by MDA-MB-231 cells. Compared to bare ZnO NPs, RGD-targeting of the ZnO NPs to integrin αvβ3 receptors expressed on MDA-MB-231 cells appears to increase the toxicity of the ZnO NPs to breast cancer cells at lower doses. Confocal microscopy of live MDA-MB-231 cells confirms uptake of both classes of ZnO NPs with a commensurate rise in intracellular Zn(2+) concentration prior to cell death. The response of the cells within the population to intracellular Zn(2+) is highly heterogeneous. In addition, the results emphasize the utility of dynamic and quantitative imaging in understanding cell uptake and processing of targeted therapeutic ZnO NPs at the cellular level by heterogeneous cancer cell populations, which can be crucial for the development of optimized treatment strategies.
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http://dx.doi.org/10.1002/adhm.201501012DOI Listing
June 2016

A novel method for quantifying spatial correlations between patterns of atherosclerosis and hemodynamic factors.

J Biomech Eng 2013 Feb;135(2):021023

Department of Aeronautics and Department of Bioengineering, Imperial College London, London, UK.

Studies investigating the relation between the focal nature of atherosclerosis and hemodynamic factors are employing increasingly rigorous approaches to map the disease and calculate hemodynamic metrics. However, no standardized methodology exists to quantitatively compare these distributions. We developed a statistical technique that can be used to determine if hemodynamic and lesion maps are significantly correlated. The technique, which is based on a surrogate data analysis, does not require any assumptions (such as linearity) on the nature of the correlation. Randomized sampling was used to ensure the independence of data points, another basic assumption of commonly-used statistical methods that is often disregarded. The novel technique was used to compare previously-obtained maps of lesion prevalence in aortas of immature and mature cholesterol-fed rabbits to corresponding maps of wall shear stress, averaged across several animals in each age group. A significant spatial correlation was found in the proximal descending thoracic aorta, but not further downstream. Around intercostal branch openings the correlation was borderline significant in immature but not in mature animals. The results confirm the need for further investigation of the relation between the localization of atherosclerosis and blood flow, in conjunction with appropriate statistical techniques such as the method proposed here.
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http://dx.doi.org/10.1115/1.4023381DOI Listing
February 2013

Patch-based automatic retinal vessel segmentation in global and local structural context.

Annu Int Conf IEEE Eng Med Biol Soc 2012 ;2012:4942-5

Bioengineering Department, Imperial College London, South Kensington Campus, London SW7 2AZ.

In this paper, we extend our published work [1] and propose an automated system to segment retinal vessel bed in digital fundus images with enough adaptability to analyze images from fluorescein angiography. This approach takes into account both the global and local context and enables both vessel segmentation and microvascular centreline extraction. These tools should allow researchers and clinicians to estimate and assess vessel diameter, capillary blood volume and microvascular topology for early stage disease detection, monitoring and treatment. Global vessel bed segmentation is achieved by combining phase-invariant orientation fields with neighbourhood pixel intensities in a patch-based feature vector for supervised learning. This approach is evaluated against benchmarks on the DRIVE database [2]. Local microvascular centrelines within Regions-of-Interest (ROIs) are segmented by linking the phase-invariant orientation measures with phase-selective local structure features. Our global and local structural segmentation can be used to assess both pathological structural alterations and microemboli occurrence in non-invasive clinical settings in a longitudinal study.
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http://dx.doi.org/10.1109/EMBC.2012.6347101DOI Listing
August 2013

Segmentation of endothelial cell boundaries of rabbit aortic images using a machine learning approach.

Int J Biomed Imaging 2011 28;2011:270247. Epub 2011 Jun 28.

Department of Bioengineering, Imperial College London, London SW7 2AZ, UK.

This paper presents an automatic detection method for thin boundaries of silver-stained endothelial cells (ECs) imaged using light microscopy of endothelium mono-layers from rabbit aortas. To achieve this, a segmentation technique was developed, which relies on a rich feature space to describe the spatial neighbourhood of each pixel and employs a Support Vector Machine (SVM) as a classifier. This segmentation approach is compared, using hand-labelled data, to a number of standard segmentation/thresholding methods commonly applied in microscopy. The importance of different features is also assessed using the method of minimum Redundancy, Maximum Relevance (mRMR), and the effect of different SVM kernels is also considered. The results show that the approach suggested in this paper attains much greater accuracy than standard techniques; in our comparisons with manually labelled data, our proposed technique is able to identify boundary pixels to an accuracy of 93%. More significantly, out of a set of 56 regions of image data, 43 regions were binarised to a useful level of accuracy. The results obtained from the image segmentation technique developed here may be used for the study of shape and alignment of ECs, and hence patterns of blood flow, around arterial branches.
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http://dx.doi.org/10.1155/2011/270247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3132519PMC
November 2011

Morphological evidence for a change in the pattern of aortic wall shear stress with age.

Arterioscler Thromb Vasc Biol 2011 Mar 4;31(3):543-50. Epub 2011 Jan 4.

Department of Bioengineering, Imperial College London, London, United Kingdom.

Objective: The distribution of atherosclerosis around branch sites changes with age in human and rabbit aortas. We tested whether that reflects a change in the pattern of wall shear stress by examining shear-dependent morphological features of endothelial cells.

Methods And Results: Endothelial cells and their nuclei align and elongate with applied shear. These parameters were examined in the descending thoracic aorta of immature and mature rabbits. The use of Häutchen preparations, fluorescent stains, and automated image analysis allowed nuclear morphology to be mapped reliably at high resolution over large areas. Cells and their nuclei were most elongated downstream of branch ostia in immature aortas but upstream of them in mature aortas. Elongation was generally greater in mature animals, and nuclei aligned toward the ostia more in these animals, consistent with a greater flow into the branch. Morphology away from branches was indicative of helical flow in the aorta, with greatest shear on the dorsal wall, at both ages.

Conclusions: The data are consistent with age-related changes in the pattern of shear around aortic branches. Maps of nuclear elongation closely resembled maps of lesion frequency. The association was positive, implying that lesions occur at sites of high shear stress at both ages.
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http://dx.doi.org/10.1161/ATVBAHA.110.219683DOI Listing
March 2011

A numerical study of red-green colour opponent properties in the primate retina.

Eur J Neurosci 2007 Feb;25(4):1155-65

Department of Bioengineering, Imperial College London, Exhibition Road, London SW7 2AZ, UK.

It remains an important question whether neural function is mediated entirely by its tailored circuitry. A persistent debate in retinal colour vision is whether the centre and the surround of a ganglion cell receptive field receive dominant inputs either from L or M cones in an antagonistic manner (the selective wiring model) or mixed inputs (the mixed wiring model). Despite many anatomical, physiological and psychophysical experiments, a decisive conclusion has not been reached. An in-depth examination of what the pure mixed wiring mechanisms predicts is therefore important. These two models make different predictions both for the fovea and for the peripheral retina. Recently, a dynamic cellular model of the primate fovea was developed [Momiji et al. (2006) Vis. Res., 46, 365-381]. Unlike earlier models, it explicitly incorporates spatial non-uniformities, such as the random arrangement of L and M cones. Here, a related model is developed for the peripheral retina by incorporating anatomically reasonable degrees of convergence between cones, bipolar cells and ganglion cells. These two models, in which selective wiring mechanisms are absent, are applied to describe both foveal and peripheral colour vision. In numerical simulations, peripheral ganglion cells are less colour sensitive than foveal counterparts, but none-the-less display comparative sensitivities. Furthermore, peripheral colour sensitivity increases with temporal frequency, relative to foveal sensitivity. These results are congruent with recent physiological experiments.
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http://dx.doi.org/10.1111/j.1460-9568.2007.05362.xDOI Listing
February 2007

Segmentation of blood vessels from red-free and fluorescein retinal images.

Med Image Anal 2007 Feb 3;11(1):47-61. Epub 2007 Jan 3.

Department of Computer Science, Institute of Research in Applied Mathematics and Systems, UNAM, Apdo. Postal 20-726, México, DF 01000, Mexico.

The morphology of the retinal blood vessels can be an important indicator for diseases like diabetes, hypertension and retinopathy of prematurity (ROP). Thus, the measurement of changes in morphology of arterioles and venules can be of diagnostic value. Here we present a method to automatically segment retinal blood vessels based upon multiscale feature extraction. This method overcomes the problem of variations in contrast inherent in these images by using the first and second spatial derivatives of the intensity image that gives information about vessel topology. This approach also enables the detection of blood vessels of different widths, lengths and orientations. The local maxima over scales of the magnitude of the gradient and the maximum principal curvature of the Hessian tensor are used in a multiple pass region growing procedure. The growth progressively segments the blood vessels using feature information together with spatial information. The algorithm is tested on red-free and fluorescein retinal images, taken from two local and two public databases. Comparison with first public database yields values of 75.05% true positive rate (TPR) and 4.38% false positive rate (FPR). Second database values are of 72.46% TPR and 3.45% FPR. Our results on both public databases were comparable in performance with other authors. However, we conclude that these values are not sensitive enough so as to evaluate the performance of vessel geometry detection. Therefore we propose a new approach that uses measurements of vessel diameters and branching angles as a validation criterion to compare our segmented images with those hand segmented from public databases. Comparisons made between both hand segmented images from public databases showed a large inter-subject variability on geometric values. A last evaluation was made comparing vessel geometric values obtained from our segmented images between red-free and fluorescein paired images with the latter as the "ground truth". Our results demonstrated that borders found by our method are less biased and follow more consistently the border of the vessel and therefore they yield more confident geometric values.
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http://dx.doi.org/10.1016/j.media.2006.11.004DOI Listing
February 2007

Numerical study of short-term afterimages and associate properties in foveal vision.

Vision Res 2006 Feb 16;46(3):365-81. Epub 2005 Nov 16.

Department of Bioengineering, Imperial College London, Exhibition Road, London SW7 2AZ, UK.

A cellular model of the primate retina has been developed. Unlike existing models, it incorporates spatial non-uniformities, such as the random arrangement of L and M cones, and the radial dilation with eccentricity. Based on a population of ganglion cell activities, colour-image representation is modelled with the luminance and the R-G opponent channels. The developed model reproduces experimentally known properties in temporal and spatial vision. Furthermore, spatio-temporally coupled properties such as transition from positive to negative phases in an afterimage, are recapped. In colour vision, the model can explain the insensitivity in our colour perception to the L/M cone ratio.
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http://dx.doi.org/10.1016/j.visres.2005.08.031DOI Listing
February 2006

Carotid artery wall motion estimated from B-mode ultrasound using region tracking and block matching.

Ultrasound Med Biol 2003 Mar;29(3):387-99

Department of Biological and Medical Systems, Imperial College of Science, Technology and Medicine, London, UK.

The motion of the carotid atheromatous plaque relative to the adjacent wall may be related to the risk of cerebral events. A quantitative method for motion estimation was applied to analyse arterial wall movement from sequences of 2-D B-mode ultrasound (US) images. Image speckle patterns were tracked between successive frames using the correlation coefficient as the matching criterion. The size of the selected region-of-interest (ROI) was shown to affect the motion analysis results; an optimal size of 3.2 x 2.5 mm(2) was suggested for tracking a region at the wall-lumen interface and of 6.3 x 2.5 mm(2) for one within the tissue. The results showed expected cyclical motion in the radial direction and some axial movement of the arterial wall. The method can be used to study further the axial motion of the carotid artery wall and plaque and, thus, provide useful insight into the mechanisms of atherosclerosis.
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http://dx.doi.org/10.1016/s0301-5629(02)00760-3DOI Listing
March 2003

Retinal vascular tree morphology: a semi-automatic quantification.

IEEE Trans Biomed Eng 2002 Aug;49(8):912-7

Department of Computer Science, Institute of Research in Applied Mathematics and Systems (IIMAS), Universidad Nacional Autonoma de Mexico, Circuito Escolar Ciudad Universitaria, México, DF.

A semi-automatic method to measure and quantify geometrical and topological properties of continuous vascular trees in clinical fundus images is described. Measurements are made from binary images obtained with a previously described segmentation process. The skeletons of the segmented trees are produced by thinning,ff branch and crossing points are identified and segments of the trees are labeled and stored as a chain code. The operator selects a tree to be measured and decides if it is an arterial or venous tree. An automatic process then measures the lengths, areas and angles of the individual segments of the tree. Geometrical data and the connectivity information between branches from continuous retinal vessel trees are tabulated. A number of geometrical properties and topological indexes are derived. Vessel diameters and branching angles are validated against manual measurements and several derived geometrical and topological properties are extracted from red-free fundus images of ten normotensive and ten age- and sex-matched hypertensive subjects and compared with previously reported results.
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http://dx.doi.org/10.1109/TBME.2002.800789DOI Listing
August 2002