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    ABSTRACT: Multiexponential decay parameters are estimated from diffusion-weighted-imaging that generally have inherently low signal-to-noise ratio and non-normal noise distributions, especially at high b-values. Conventional nonlinear regression algorithms assume normally distributed noise, introducing bias into the calculated decay parameters and potentially affecting their ability to classify tumors. This study aims to accurately estimate noise of averaged diffusion-weighted-imaging, to correct the noise induced bias, and to assess the effect upon cancer classification. A new adaptation of the median-absolute-deviation technique in the wavelet-domain, using a closed form approximation of convolved probability-distribution-functions, is proposed to estimate noise. Nonlinear regression algorithms that account for the underlying noise (maximum probability) fit the biexponential/stretched exponential decay models to the diffusion-weighted signal. A logistic-regression model was built from the decay parameters to discriminate benign from metastatic neck lymph nodes in 40 patients. The adapted median-absolute-deviation method accurately predicted the noise of simulated (R(2) = 0.96) and neck diffusion-weighted-imaging (averaged once or four times). Maximum probability recovers the true apparent-diffusion-coefficient of the simulated data better than nonlinear regression (up to 40%), whereas no apparent differences were found for the other decay parameters. Perfusion-related parameters were best at cancer classification. Noise-corrected decay parameters did not significantly improve classification for the clinical data set though simulations show benefit for lower signal-to-noise ratio acquisitions. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 06/2014; 71(6). DOI:10.1002/mrm.24877
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    ABSTRACT: Genetically expressed fluorescent proteins have been shown to provide photoacoustic contrast. However, they can be limited by low photoacoustic generation efficiency and low optical absorption at red and near infrared wavelengths, thus limiting their usefulness in mammalian small animal models. In addition, many fluorescent proteins exhibit low photostability due to photobleaching and transient absorption effects. In this study, we explore these issues by synthesizing and characterizing a range of commonly used fluorescent proteins (dsRed, mCherry, mNeptune, mRaspberry, AQ143, E2 Crimson) and novel non-fluorescent chromoproteins (aeCP597 and cjBlue and a non-fluorescent mutant of E2 Crimson). The photoacoustic spectra, photoacoustic generation efficiency and photostability of each fluorescent protein and chromoprotein were measured. Compared to the fluorescent proteins, the chromoproteins were found to exhibit higher photoacoustic generation efficiency due to the absence of radiative relaxation and ground state depopulation, and significantly higher photostability. The feasibility of converting an existing fluorescent protein into a non-fluorescent chromoprotein via mutagenesis was also demonstrated. The chromoprotein mutant exhibited greater photoacoustic signal generation efficiency and better agreement between the photoacoustic and the specific extinction coefficient spectra than the original fluorescent protein. Lastly, the genetic expression of a chromoprotein in mammalian cells was demonstrated. This study suggests that chromoproteins may have potential for providing genetically encoded photoacoustic contrast.
    Biomedical Optics Express 11/2013; 4(11):2477-2490. DOI:10.1364/BOE.4.002477
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    ABSTRACT: Epidural catheters are used to deliver anesthetics and opioids for managing pain in many clinical scenarios. Currently, epidural catheter insertion is performed without information about the tissues that are directly ahead of the catheter. As a result, the catheter can be incorrectly positioned within a blood vessel, which can cause toxicity. Recent studies have shown that optical reflectance spectroscopy could be beneficial for guiding needles that are used to insert catheters. In this study, we investigate the whether this technique could benefit the placement of catheters within the epidural space. We present a novel optical epidural catheter with integrated polymer light guides that allows for optical spectra to be acquired from tissues at the distal tip. To obtain an initial indication of the information that could be obtained, reflectance values and photon penetration depth were estimated using Monte Carlo simulations, and optical reflectance spectra were acquired during a laminectomy of a swine ex vivo. Large differences between the spectra acquired from epidural adipose tissue and from venous blood were observed. The optical catheter has the potential to provide real-time detection of intravascular catheter placement that could reduce the risk of complications.
    Biomedical Optics Express 11/2013; 4(11):2619-2628. DOI:10.1364/BOE.4.002619
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    ABSTRACT: Gold nanoparticles (GNPs) may be used as a contrast agent to identify tumour location and can be modified to target and image specific tumour biological parameters. There are currently no imaging systems in the literature that have sufficient sensitivity to GNP concentration and distribution measurement at sufficient tissue depth for use in in vivo and in vitro studies. We have demonstrated that high detecting sensitivity of GNPs can be achieved using x-ray fluorescence; furthermore this technique enables greater depth imaging in comparison to optical modalities. Two x-ray fluorescence systems were developed and used to image a range of GNP imaging phantoms. The first system consisted of a 10 mm(2) silicon drift detector coupled to a slightly focusing polycapillary optic which allowed 2D energy resolved imaging in step and scan mode. The system has sensitivity to GNP concentrations as low as 1 ppm. GNP concentrations different by a factor of 5 could be resolved, offering potential to distinguish tumour from non-tumour. The second system was designed to avoid slow step and scan image acquisition; the feasibility of excitation of the whole specimen with a wide beam and detection of the fluorescent x-rays with a pixellated controlled drift energy resolving detector without scanning was investigated. A parallel polycapillary optic coupled to the detector was successfully used to ascertain the position where fluorescence was emitted. The tissue penetration of the technique was demonstrated to be sufficient for near-surface small-animal studies, and for imaging 3D in vitro cellular constructs. Previous work demonstrates strong potential for both imaging systems to form quantitative images of GNP concentration.
    Physics in Medicine and Biology 10/2013; 58(21):7841-7855. DOI:10.1088/0031-9155/58/21/7841
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    ABSTRACT: PurposeMyocardial blood flow (MBF) is an important indicator of cardiac tissue health, which can be measured using arterial spin labeling. This study aimed to develop a new method of MBF quantification with blood pool magnetization measurement (bpMBF quantification) that allows multislice cardiac arterial spin labeling. Theory and MethodsA multislice segmented ECG-gated Look-Locker T-1 mapping sequence was validated. Quantification of multislice arterial spin labeling is not straightforward due to the large volume of blood inverted following slice-selective inversion. For bpMBF quantification, a direct measurement of the left-ventricle blood pool magnetization was used to approximate the blood input function into the Bloch equations. Simulations and in vivo measurements in the mouse heart were performed to evaluate the bpMBF method. ResultsMeasurements indicated that blood pool magnetization requires approximate to 3 s to return to equilibrium following slice-selective inversion. Simulation and in vivo results show that bpMBF quantification is robust to variations in slice-selective thickness and therefore applicable to multislice acquisition, whereas traditional methods are likely to underestimate multislice perfusion. In vivo, single and multislice perfusion values matched well when quantified using bpMBF. Conclusion The first multislice cardiac arterial spin labeling technique has been presented, which can be used for accurate perfusion measurements in studies of cardiac disease. Magn Reson Med, 70:1125-1136, 2013. (c) 2012 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 10/2013; 70(4). DOI:10.1002/mrm.24545
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    ABSTRACT: The value and distribution of calcium/phosphorus (Ca/P) ratio in bone vary between healthy and osteoporotic bone. The purpose of this study was the development of a technique for the assessment of the 3D spatial distribution of Ca/P ratio in bone apatite, which could eventually be implemented through a conventional computed tomography (CT) system. A three-material mass-fraction decomposition CT dual energy analysis was optimized. The technique was validated using ten bone phantoms of different, known Ca/P ratio. Their measured average Ca/P ratio showed a mean/maximum deviation from the expected Ca/P ratio of 0.24/0.35. Additionally, three healthy and three inflammation-mediated osteoporotic (IMO) collagen-free rabbit tibia bone samples were assessed, providing promising preliminary results on real bone tissue. The average Ca/P ratios in all IMO samples (1.64-1.65) were found to be lower than in healthy samples (1.67-1.68). Osteoporotic regions in IMO samples were located using Ca/P ratio colour maps and Ca/P ratio values as low as 1.40 ± 0.26 were found. The low Ca/P ratio volume proportion in IMO samples (12.8%-13.9%) was found to be higher than in healthy (5.8%-8.3%) samples. A region growing technique showed a higher homogeneity of Ca/P ratio in healthy than in IMO bone samples.
    Physiological Measurement 09/2013; 34(11):1399-1410. DOI:10.1088/0967-3334/34/11/1399
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    ABSTRACT: Purpose: To provide an x-ray phase contrast imaging (XPCI) method working with conventional sources that could be readily translated into clinical practice. XPCI shows potential in synchrotron studies but attempts at translating it for use with conventional sources are subject to limitations in terms of field of view, stability, exposure time, and possibly most importantly, delivered dose.Methods: Following the adaptation of our "edge-illumination" XPCI technique for use with conventional x-ray sources through the use of x-ray masks, the authors have further modified the design of such masks to allow further reducing the dose delivered to the sample without affecting the phase sensitivity of the method.Results: The authors have built a prototype based on the new mask design and used it to image ex vivo breast tissue samples containing malignant lesions. The authors compared images acquired with this prototype to those obtained with a conventional system. The authors demonstrate and quantify image improvements, especially in terms of microcalcification detection. On calcifications detected also by the conventional system, the authors measure contrast increases from five to nine fold; calcifications and other features were also detected which are completely invisible in the conventional image. Dose measurements confirmed that the above enhancements were achieved while delivering doses compatible with clinical practice.Conclusions: The authors obtained phase-related image enhancements in mammography by means of a system built with components available off-the-shelf that operates under exposure time and dose conditions compatible with clinical practice. This opens the way to a straightforward translation of phase enhanced imaging methods into clinical practice.
    Medical Physics 09/2013; 40(9):090701. DOI:10.1118/1.4817480
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    ABSTRACT: Here we present a general alignment algorithm for an edge illumination x-ray phase contrast imaging system, which is used with the laboratory systems developed at UCL. It has the flexibility to be used with all current mask designs, and could also be applied to future synchrotron based systems. The algorithm has proved to be robust experimentally, and can be used for the automatization of future commercial systems through automatic alignment and alignment correction. (C) 2013 AIP Publishing LLC.
    The Review of scientific instruments 08/2013; 84(8):083702. DOI:10.1063/1.4816827
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    ABSTRACT: This study was designed to determine the reproducibility of optical mammography. Eight healthy pre-menopausal volunteers were scanned at different time intervals (minutes, weeks and months apart) to investigate the effects of within-subject variation, between-subject variation and systematic variations on both the raw data and images. The study shows that the greatest source of variation in optical mammography raw data and images is between different subjects, and scans of the same subject are very reproducible. The averaged total haemoglobin concentration from the eight volunteers was (24 ± 10) µM, and the average tissue oxygen saturation was (70 ± 10)%, which is comparable with other data in the literature. The average absorption coefficient at 780 nm was (0.0048 ± 0.0017) mm(-1) and the average reduced scatter coefficient at 780 nm was (0.80 ± 0.12) mm(-1). Again, this is comparable with published values. When our data are combined with the published values, the weighted average total haemoglobin concentration and tissue oxygen saturation for pre-menopausal breasts are (29 ± 8) µM and (73 ± 3)%, respectively. The results of our study show that we can be reassured that any changes within the tumour region seen during neoadjuvant therapy are likely to be due to a real physiological response to treatment, as the physiological properties of the breast remain relatively constant. However, in this study, we cannot distinguish between a tumour response to treatment and systemic changes in the healthy breast.
    Physics in Medicine and Biology 06/2013; 58(13):4579-4594. DOI:10.1088/0031-9155/58/13/4579
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    ABSTRACT: The redox state of cerebral mitochondrial cytochrome c oxidase monitored with near-infrared spectroscopy (Δ[oxCCO]) is a signal with strong potential as a non-invasive, bedside biomarker of cerebral metabolic status. We hypothesised that the higher mitochondrial density of brain compared to skin and skull would lead to evidence of brain-specificity of the Δ[oxCCO] signal when measured with a multi-distance near-infrared spectroscopy (NIRS) system. Measurements of Δ[oxCCO] as well as of concentration changes in oxygenated (Δ[HbO2]) and deoxygenated haemoglobin (Δ[HHb]) were taken at multiple source-detector distances during systemic hypoxia and hypocapnia (decrease in cerebral oxygen delivery), and hyperoxia and hypercapnia (increase in cerebral oxygen delivery) from 15 adult healthy volunteers. Increasing source-detector spacing is associated with increasing light penetration depth and thus higher sensitivity to cerebral changes. An increase in Δ[oxCCO] was observed during the challenges that increased cerebral oxygen delivery and the opposite was observed when cerebral oxygen delivery decreased. A consistent pattern of statistically significant increasing amplitude of the Δ[oxCCO] response with increasing light penetration depth was observed in all four challenges, a behaviour that was distinctly different from that of the haemoglobin chromophores, which did not show this statistically significant depth gradient. This depth-dependence of the Δ[oxCCO] signal corroborates the notion of higher concentrations of CCO being present in cerebral tissue compared to extracranial components and highlights the value of NIRS-derived Δ[oxCCO] as a brain-specific signal of cerebral metabolism, superior in this aspect to haemoglobin.
    NeuroImage 05/2013; 85(Pt 1). DOI:10.1016/j.neuroimage.2013.05.070
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