The Computer Journal 2009 Greenspan 43 63

# The Author 2008. Published by Oxford University Press on behalf of The British Computer Society. All rights reserved.
Advance Access publication on February 19, 2008
For Permissions, please email: journals.permissions@oxfordjournals.org doi:10.1093/comjnl/bxm075
Super-Resolution in Medical Imaging

HAYIT GREENSPAN *
Faculty of Engineering, Biomedical Engineering Department, Tel-Aviv University, Tel-Aviv, Israel *Corresponding author: hayit@eng.tau.ac.il This paper provides an overview on super-resolution (SR) research in medical imaging applications. Many imaging modalities exist. Some provide anatomical information and reveal information about the structure of the human body, and others provide functional information, locations of activity for specic activities and specied tasks. Each imaging system has a characteristic resolution, which is determined based on physical constraints of the system detectors that are in turn tuned to signal-to-noise and timing considerations. A common goal across systems is to increase the resolution, and as much as possible achieve true isotropic 3-D imaging. SR technology can serve to advance this goal. Research on SR in key medical imaging modalities, including MRI, fMRI and PET, has started to emerge in recent years and is reviewed herein. The algorithms used are mostly based on standard SR algorithms. Results demonstrate the potential in introducing SR techniques into practical medical applications. Keywords: medical imaging; super-resolution; MRI; PET Received 6 August 2006; revised 6 June 2007
Downloaded from http://comjnl.oxfordjournals.org/ at Indian Institute of Technology Roorkee on January 26, 2013
1.
INTRODUCTION
The main goal of medical imaging is to extract a 3-D modeling of the human body or specic organs within it. To accomplish this goal, various imaging modalities have been developed over the years, each based on a particular energy source that passes through the body. Many imaging modalities exist, with some providing anatomical information and revealing information about the structure, and others providing functional information, e.g. revealing locations of activity within the brain for specic activities and specied tasks. The medical imaging eld is rapidly evolving in increased resolution machines and advanced content-processing tools [1]. Medical imaging system developers strive to increase resolution since higher resolution is the key to more accurate understanding of the anatomy, it can support early detection of abnormalities and can increase the accuracy in the assessment of size and morphology of organs and pathologies. In recent years, several research groups have started to address the goal of resolution augmentation in medical imagery as a software post-processing challenge, rather than a medical hardware-engineering task. The motivation for this initiative emerged following major advances in the domains of image and video processing that indicated the possibility of augmenting resolution using what are known as super-resolution (SR) algorithms. SR deals with the task of using several low-resolution (LR) images from a particular imaging system to estimate, or reconstruct, the high-resolution (HR) source. Each LR input image focuses on a slightly
shifted eld-of-view [or point-of-view (POV)] of the HR scene. A variety of reconstruction algorithms have been proposed in the literature, where the common goal is to estimate the HR source as accurately as possible, while minimizing noise and preserving important image constraints, including image smoothness and more recently, additional priorknowledge about the source. In 2001 and 2002, initial attempts were made to adapt SR algorithms from the computer-vision community to medical imagery applications. Initial research dealt with the magnetic resonance imaging (MRI) modality [2, 3]. Results were encouraging and were reproduced around the world within the same modalities as well as additional ones, including functional MRI (fMRI) [4] and positron emission tomography (PET) [5, 6]. The goal of the current paper is to review several of the key studies that focus on SR algorithms in medical applications. Following are the key observations that may be made from the current overview. Research in the eld has so far been in what can be dened as a hypothesis testing phase: the investigation of a selected imaging modality and its evaluation as a candidate for SR, and the application of a standard SR algorithm (selected from the literature) to a specic medical task. Results are encouraging, for the MRI variants, and PET modalities. Experiments are conducted on phantoms as well as real patient data. Results are more substantial on the phantom
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H. GREENSPAN the energy acquisition process, various algorithmic transformations are used, such as the inverse Radon transform (e.g. in CT), to reconstruct a visual image. The target of a successful acquisition process is a high spatial-resolution visual image of the organ of interest. Additional characteristics of interest include a high-contrast and a high dynamic-range as well as a strong signal-to-noise ratio (SNR) output from the imaging system. A complete physical and signal-processing review of the various medical imaging modalities is beyond the scope of this paper (several books can be found, including [7 10]). Below, we briey introduce several key imaging modalities and present representative output images. Additional detail for each modality is given in Appendix A. MRI is an imaging technique used primarily in medical settings to produce high-quality images of the human body. It is based on the absorption and emission of energy in the RF range of the electromagnetic spectrum, producing images based on spatial variations in the frequency of the RF energy being absorbed and emitted by the imaged object. A sample MRI scanner and an MR reconstructed image of the human head are shown in Fig. 3a and b, respectively. A set of MRI brain scans, from three standard MR imaging sequences, termed T1, T2 and Proton-Density (Pd) (see Appendix A), are shown in Fig. 4. We note that each such sequence displays a unique image of the imaged organ (brain). A standard coordinate system was developed to represent three (2-D) slice directions, as displayed in the gure. The dened slice directions will be used throughout the experiments reviewed in this paper. In addition to the standard, anatomical MR imaging, several variants exist, including the following: MRI Angiography deals with the imaging of the owing blood in the arteries and veins of the body, with intensity proportional to the velocity of the ow. MRI Angiography can be used to evaluate abnormal narrowing of the blood vessels (stenosis) and their risk of rapture (aneurysms). Diffusion-weighted imaging (DWI) is an MRI modality that produces the in vivo MR images of biological tissues weighted with the local characteristics of water diffusion. DWIs are very useful in diagnosing vascular strokes in the brain and to study white matter diseases. Diffusion tensor imaging (DTI) is a variation of DWI in which at least seven images are acquired for every slice, with at least six directions of diffusion weighting. DTI serves as a unique tool for visualization of the direction and intactness of white matter ber tracts in vivo by identifying the preferred direction of diffusion. HR DTI combined with algorithms for tracing bers in three dimensions in tensor elds has the potential to enable ber tract mapping of critical functional pathways in the brain. The clinical applications are the tract-specic localization of white matter lesions, the localization of tumors relative to the white matter tracts and the localization of the main white matter tracts for neurosurgical planning. fMRI measures the changes in blood ow
data. Real data scenarios introduce various artifacts that need to be addressed, patient motion difculties as well as acquisition time constraints. A comparison across several currently published SR variants algorithmic variants does not reveal major differences. Future major challenges in this eld include: on the theoretical front, the development of novel SR algorithms that combine medical image prior knowledge as regularization terms in the SR process. On the applicative front, the shift to the clinical settings, an important next step to dene the contribution of SR in the medical eld. In the rest of this introduction we introduce the non-medical reader to the variety of medical imaging modalities as well as introduce resolution-related challenges in the medical imaging eld. A brief overview of the SR algorithms, SR parameterization, and evaluation schemes are given in Section 2. Section 3 focuses on the application of SR in MRI, and Section 4 describes major works on the application of SR in PET. Key issues and an overview of the outstanding challenges in this domain nalize this overview paper, in Section 5. 1.1. Medical imaging acquisition process and clinical signicance
Figure 1 illustrates the general medical imagery acquisition process. Energy is acquired as it transverses the body (or organ) as part of a transmission or an emission process. For example, in X-ray computer tomography (CT), X-rays are transmitted through the body and captured by an array of detectors, following attenuation by the imaged object. In PET, photons are emitted from within the body (from radioactive molecules inserted into the body) and are then detected by an array of detectors. The energy is captured by an array of detectors that are designed per specic imaging modality [e.g. radio frequency (RF) coils in MRI, crystal detectors in PET]. Figure 2 presents a schematic description of an X-ray transmission (a) and a photon emission process (b). Following
FIGURE 1. Illustration of the general medical imagery acquisition process.
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FIGURE 2. Schematic description of x-ray transmission and PET acquisitions. (a) X-ray CT acquisition via X-ray transmission. (b) Schematics of PET acquisition via photon emission. The PET camera is comprised of a ring of discrete detectors. Shown on the left is a pair of opposing PET detectors. Each such detector pair detects coincident photon pair emission.
and blood oxygenation in the brain (hemodynamics), which is correlated to neural activity in the brain or spinal cord of humans or other animals. The magnetic resonance (MR) signal of blood is slightly different depending on the level of oxygenation. These differential signals can be detected using an appropriate MR pulse sequence. Figure 3 presents examples of an angiographic image (c), a DTI image (d) and an fMRI image (e). X-ray CT is based on the fact that X-rays can traverse a crosssection of an object along straight lines, be attenuated by the object, and detected outside it (Fig. 2a). Since its introduction in the 1970s, CT has become an important tool in medical
FIGURE 3. The MRI modality. (a) MRI scanner (GE medical systems). (b) Anatomical image of a head. T1-weighted. (c) Angiography. (d) DTI. 150 gradient directions. (e) fMRI. Activated areas overlayed on the anatomical image (for color see Figure 12).
imaging in the diagnosis of a large number of different disease entities. CT is currently a standard diagnosis tool in several domains, including: head imaging in particular for diagnosis of cerebrovascular accidents and intracranial hemorrhage; facial and skull fractures evaluation; surgical planning for craniofacial and dentofacial deformities; detecting acute and chronic chest diseases; imaging of coronary arteries (cardiac CT angiography); abdominal diseases; imaging complex fractures especially around joints, and more. Recently, CT is also being considered for preventive medicine or screening for disease, for example CT colonography for patients with a high risk of colon cancer. The CT scanner can image complete organs and volumes using a large series of two-dimensional x-ray images taken around a single axis of rotation. Over recent years, a transition has been made from slice-by-slice imaging to volume imaging, with the introduction of spiral scan modes. An example CT image is shown in Fig. 6a. PET belongs to the radiology specialty of nuclear medicine, and it provides information on the distribution of a chosen molecule inside the human body (Fig. 2b). PET provides functional information that is complimentary to the anatomical information from other radiological imaging techniques such as the MRI and CT. In particular, PET is emerging as an important tool to detect tumors and to evaluate their degree of malignancy, based on differences in biochemistry and metabolism between tumors and their surrounding normal tissues [11]. PET is also used for functional brain imaging and in cardiology, to assess myocardial viability and efciency [12 15]. PET images are commonly fused with anatomical images such as CT. The need to combine PET and CT has evolved into specialized hardware that makes the task of fusing the two modalities much easier. A combined PET/CT machine is shown in Fig. 5. An example of PET image is shown in Fig. 6b and a combined PET/CT image is shown in Fig. 6c. For an overview on PET, see [16].
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FIGURE 4. Brain slices in varying MRI sequences (taken from BrainWeb [17]). Transverse slices are in the xy plane. Sagittal slices are in the zy plane. Coronal slices are in the zx plane.
FIGURE 5. Combined CT/PET scanners. (a) Illustration. (b) Scanner (GE medical systems).
FIGURE 6. Example brain scans. (a) CT image. (b) PET image. (c) PET and CT images fused together.
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Resolution limitations and challenges in medical imaging
A common goal in all medical imaging systems is to increase the resolution and, to the extent possible, achieve true isotropic 3-D imaging. To capture the entire frequency content of the imaged object, a sampling rate at the Nyquist frequency is required, dened as twice the highest frequency present in the imaged object. Correspondingly, the sampling distance must be one-half the spatial resolution, dened as the distance between half-value points of the system impulse response, or the full-width-at-half-maximum (FWHM). In practice, the range of frequencies captured is limited by the maximal sampling frequency of the imaging device detectors, as dened by the detector pitch, or the detector spacing. Reduced size (width) of detectors and smaller inter-detector distances can provide increased resolution, but this is at the cost of an increase in the noise, thus results in a much-reduced SNR. The sensor resolution of a general imaging system is determined according to the physical constraints of the detectors, which are in turn tuned to SNR and timing considerations in the system. Within each imaging modality, specic physical laws are in control, dening the meaning of noise and the sensitivity of the imaging process. Signal processing rules govern the system design in an attempt to achieve an acceptable compromise between resolution and SNR. The resolution limitations in MRI and PET will be dened in depth in Sections 3 and 4, respectively. A resolution-related challenge in medical image processing is known as partial volume effect (PVE), which arises when an interface between two different tissues occur within a single voxel. The PVE is a direct consequence of limited resolution during the acquisition process. In general, PVE blurs the boundary between tissues and adds complexity to tissue characterizations. In MRI, the resulting image pixels display a gray level proportional to the weighted average of the signals stemming from neighboring tissues. The exact location of boundaries may be shifted thus introducing a major obstacle for anatomical MRI brain segmentation. In a CT image, each voxel represents the attenuation properties of a specic volume. When more than a single tissue is present within the voxel, the value will be some (nonlinear) average of the tissues attenuation properties. In DTI, where isotropic resolution is particularly important, PVEs are a limiting factor in the analysis of directional and structural axonal connectivity. Increased resolution can help overcome or reduce the problems associated with PVE.
means for extending current medical imaging resolution limitations. The goal of SR algorithms is to improve the image resolution in cases in which the image was undersampled. Such cases involve the following: rst, the imaged object has high-frequency content. Second, the sampling frequency as dened by the detectors, does not fulll the Nyquist frequency; thus, aliasing and degradation in the highfrequency content can be observed. The SR process helps overcome the detector sampling limitations by practically increasing the sampling rate, and thus utilizing additional high-frequency information and reducing the aliasing effects. Note that in cases in which no frequencies higher than half of the detectors sampling frequency exist, SR will in effect result in the averaging of noise; in such cases, no additional improvements in the image resolution can be obtained by SR.
2.
SR ALGORITHMS: BRIEF OVERVIEW
1.3.
Can SR support the medical imaging challenges?
SR reconstruction deals with combining several LR images to create a HR image. SR techniques have been suggested in recent years as a means for increasing resolution without altering the existing imaging hardware. Thus, they can be seen as a
The term SR refers here to a technique in which several LR images, from different POV relative to the image object, are combined to obtain a higher-resolution image. Several SR reconstruction methodologies have been developed in the last two decades [18]. In initial works [e.g., 19], the frequency domain was used to demonstrate the ability to reconstruct one improved resolution image from several down-sampled noisefree versions of it, based on the spatial aliasing effect. The frequency domain approach was further generalized to noisy and blurred images in [20] and a spatial domain alternative was suggested in [21]. Further non-iterative spatial domain data fusion approaches were proposed in [22, 23]. An iterative back-projection (IBP) method was proposed in [24]. This method starts with an initial guess of the outcome image, projects the initial result to simulate the LR measurements, and updates the temporary guess according to the simulation error. Further detail on the IBP method is provided in the following subsections. A set theoretic approach to SR was suggested in [25]. Here, convex sets are dened which represent tight constraints on the required image. Nonlinear constraints are combined within the restoration process and a projection onto convex sets (POCS) algorithm is utilized. A hybrid model that combines maximum-likelihood (ML) and POCS was suggested in [26]. More recent SR works aim at combining the SR approaches with regularization terms, e.g. in [27] fast and robust multi-frame SR is proposed using L1 norm minimization and robust regularization based on a bilateral prior to deal with different data and noise models. In this section, we mathematically dene the general image acquisition procedure, and present the general formalism for SR. It is our goal to provide the reader with a brief overview of specic algorithms and related parameterization issues, as related to the research works reviewed herein.
48 2.1. Modeling the image acquisition process

N fykgk 1
H. GREENSPAN The differences between the original image and the synthetically generated image are up-sampled to achieve the smaller SR pixel size, moved to a common reference frame, and averaged over K acquisitions. The symbol p is termed the BP kernel and is related to h [27] (often h is assumed to be symmetric which results in p h). The dened iterative process [equations (3) and (4)] is repeated until a predened error measure, such as the mean square error in the maximum-likelihood (ML) sense: 12 ML x
K 2 X n ~ yk y k k1
of LR images and assuming all LR images Given a set are degraded versions of the same original HR image, x, SR algorithms reconstruct a super-resolved HR image which by simulating the imaging process, results in images that best describe the LR measurements via some SR criterion. Mathematically, we can express each LR image yk as the result of a sequence of operators on the original HR image source, x, consisting of geometrical warp, blurring and decimation, as in equation (1), yk fk xh # s vk ; k f1; . . . ; N g; 1
where fk is the kth geometrical transformation of the image x to the same reference frame of acquisition for yk, h is a blur kerneloften referred to as the point spread function (PSF), dened by the properties of the lens and the imaging device, and vk is an additive noise. The symbol (*) is the convolution operator and # s represents the down sampling of an HR image to a LR grid by a factor s.
2.2.
The general formalism of SR
We present next the general formalism for SR, as relevant both for the IBP approach of Irani and Peleg [24], as well as to the more recent, ML formalism of [27]. An initial estimate of the HR image, x (0), is taken as the average of the set of LR acquisitions brought to the same reference point and up-sampled: x0
K 1X f 1 y k " s ; k k1 k
has been minimized or has reached a predened threshold. Alternatively, a maximum number of iterations has been reached. Equation (1) denes a classical restoration problem for the original HR image x. The solution to this problem depends on the minimization criterion. Equations [3, 4] describe a solution in the sense of ML estimator that minimizes the L2 norm criterion [equation (5)], which assumes an additive independent noise with normal distribution in the forward model. In [27], the solution for the general Lp norm is derived. It is shown that the L1 norm is more robust and can be used for strong sporadic noise. In SR reconstruction with MAP estimation, prior knowledge on the imaged data, or the desired reconstructed solution, is incorporated as a regularization term in the minimization process:
n 12 MAP x K 2 X n n ~ yk y k l A x ; k 1
where yk is one of K acquisitions, fk the geometric transformation to a common reference frame and " s the up-sampling operator from LR to the HR representation. Given an image-acquisition model, and an HR estimate (of the nth iteration), x (n), a set of synthetically generated LR images, n) ( fy k g, can be extracted. The process involves shifting the HR image to the kth POV, blurring to account for the psf and downsampling to the systems sampling rate. The nth LR synthetically n) ( sampled set of images fy k g is thus obtained from the nth approximation of the HR image x (n) (ignoring the noise), by:
n n ~ y k fk x h # s:
where A(x) is the regularization term providing prior information on the desired SR image x, and l is the regularization coefcient specifying the weight of the regularization term. Several regularization terms from the literature have been used in SR, including the Tikhonov cost function [26] and the bilateral lter [27].
2.3.
SR parameters and performance evaluation: general and medical domain considerations
The current iteration x (n) is updated according to the difference between the synthetically generated set of LR images n) ( fy k g and the actual acquired set of LR images fykg: xn1 xn
K 1X n ~ f 1 yk y k " sp: k k 1 k
Each SR algorithm has certain key parameters that need to be determined to most closely match with the true imaging system characteristics and specic application scenario. Two key parameters are the transformation and blur: the transformation parameter needs to enable precise image registration, accurate to a small fraction of a pixel, capable of bringing all input images to a common reference frame. In medical systems, the transformation is typically the physical shift (from an original position) between the object (patient bed) and the imager.
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The blur, h, is dened by the imaging system PSF. In medical imaging systems, the PSF is often dened as the slice excitation prole. Experiments indicate that the typical slice proles are well approximated by Gaussian functions, where the FWHM is the originally selected slice width. Two PSFs are thus commonly used to represent the blur: the rst is a rectangular pulse PSF which is a crude estimation for the slice prole (termed Box-PSF), where the box width is taken as the selected slice width (in the desired HR pixel units). The more accurate representation is the use of a Gaussian PSF (Gaussian-PSF), with FWHM set to the selected slice width. The BP parameter of equation (4), p, is ideally the inverse of the blur kernel. In [24], it was proven that the proposed SR algorithm converges with a convergence condition (for 2-D translations and rotations) given by kd 2 h * pk , 1, where d is the unity impulse function. The smaller kd 2 h * pk is the faster the algorithm converges. This criterion allows the kernel p to be other than the exact inverse of the blurring function h. For the typical slice proles mentioned above, the p lter can be taken as an impulse function, satisfying the Irani Peleg requirement for convergence. In both MRI [3] and PET studies [5], the blur h and BP kernel p were correspondingly set to unity. In [6], an increase in model accuracy is attempted by dening both the blur kernel as well as the BP kernel, to be modeled as a Gaussian PSF. In regularization-based schemes, an additional minimization parameter exists per dened objective function. Optimization of this parameter can be performed in all three spatial directions, denoted as 3-D anisotropic ltering, or in the slice select direction only, known as 1-D anisotropic ltering. Quantitative measures for any image enhancement procedure are a challenge. In general, image enhancement can be expressed as the increase in edge slope in the image plane as well as the increase in frequency content as viewed via the image power spectrum. When considering a method for resolution improvement, it is important to ensure that the SNR is not compromised. The SNR is measured by taking the mean of a high-intensity region of interest and dividing by the standard deviation of a region of noise outside the imaged object. A variation of the above measure is a contrast ratio measure, C, which denes the ratio between the average signals to the average background. Traditional alternatives to SR reconstruction include zeropadding, or sinc interpolation, and interleaving. In zeropadding, the spectral resolution is augmented by adding zeros embedded between the given samples. Padding the data with zeroes provides more frequency-domain points (improved spectral resolution), but does not improve the resolution limits as established by the given sampling rate, nor does it alter the effects of aliasing error. Interleaving is a method for achieving an HR image from a set of shifted LR images by combining the pixels, one by one, from alternating LR
image inputs, to generate a single large image. In the studies reviewed below, the two alternatives are utilized for comparison and evaluation of the SR methodology in varying medical imaging modalities.
3.
SR IN MRI
In this section, we focus on the application of SR methodologies to the MR imaging modality. We start by highlighting the key factors that limit resolution in MRI. We then present an analysis into what can be termed the SR dimensionality in MRI. An extended overview of recent works that explore the possibility of augmenting MRI resolution, using SR algorithms, is presented next. Both anatomical as well as functional MR images have been used with promising initial results. In [3], the IBP SR method was used for anatomical MRI. Results were shown on both phantom as well as human brain data and demonstrated that isotropic resolution can be achieved while preserving SNR. SR reconstruction based on the use of discontinuity-preserving regularization methods was proposed in [4] for HR fMRI image reconstruction. Results demonstrate that the use of SR may increase the ability to detect and visualize small regions of neuronal activity; moreover, the activated regions appear sharper and provide better information regarding their morphological limits and structure. 3.1. Resolution challenges in MRI
High resolution, isotropic 3-D MRI images are important for visualization of 3-D volumes in the imaged object and for early medical diagnosis. In practice, true 3-D acquisition methods are frequently not effective or possible, as is often the case in T2-weighted imaging, DWI and occasionally in MR angiography (MRA). True T2-weighting is difcult to obtain in reasonable imaging times by 3-D acquisition methods. The problem arises due to the need for long signal recovery between excitations to enable the operation of the spin-echo mechanism that provides T2 contrast (see Appendix A). Since all the spins are excited by every pulse, the recovery time cannot be utilized and the sequence takes a long time. In DWI, no 3-D technique for humans currently exists. Sequences that acquire raw data pertaining to the same slice or volume over many excitations cannot be modied to provide diffusion-weighted contrast because of phase inconsistencies resulting from physiological motion. MRA is another popular application that sometimes performs better in the 2-D rather than the 3-D version. In fMRI, temporal resolution as well as spatial resolution is important. Most 3-D acquisition procedures cannot reach the required temporal resolution necessary for appropriate statistical analysis. When the true 3-D image acquisition is not effective or possible, it is common practice to acquire a set of 2-D
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FIGURE 7. MRI slice acquisition. The resolution in the slice-select direction is lower than in the in-plane directions [3].
slices. The problem, as illustrated in Fig. 7, is that a set of 2-D slices does not give a good isotropic 3-D image. A reconstructed MR image is commonly of HR in-plane (x, y) and of much reduced resolution in the slice-select (z) direction. For example, it is common to nd reconstructed MR images of size 1 1 3 mm3. The spatial resolution in-plane (x, y) is determined by several factors, including the gradients intensity, the imaging bandwidth, the number of readout points and phase encoding steps (see Appendix A and related references). The slice thickness in MRI is determined by what is termed the slice-selection pulse, which is in turn determined by hardware limitations coupled with pulse sequence timing considerations. The challenge for SR in MRI is to increase the resolution in the slice-select dimension so as to achieve HR, isotropic, 3-D images. A further challenge is to achieve the HR outcome without decreasing the SNR.
FIGURE 8. Investigating SR dimensionality in MRI. Spectrum analysis (y,z) plane, Horizontal axis is the slice-select (z) direction. Top row: LR input (left) with spectrum (right). Bottom row: HR output (left) and spectrum (right) [3].
3.2.
SR dimensionality
Several works have used theoretical analysis and experimental validation, to reveal the potential for SR in MRI along with the appropriate task dimensionality [3, 28]. Signal-processing principles underlying MRI acquisition, in particular, in Fourier-encoded MRI data sets, have led researchers to acknowledge the distinct characteristics of the in-plane versus slice-select encoding. This fact, in turn, affects the effective dimensionality of the SR task. In particular, Fourierencoded in-plane MRI data is inherently band limited. This is due to the time limit of the acquisition process and the fact that the information is gathered in the frequency domain (known as k-space acquisition). In-plane shifting is thus equivalent to a global phase shift in the acquisition space (k-space), the original temporal domain, which does not affect the inherent spatial frequency resolution of the acquired data. In other words, increasing the in-plane resolution by in-plane shifting of the image is equivalent to zero-padding of the raw data in the temporal domain. A different scenario exists in the slice-select direction of a Fourier-encoded MRI. There is
sufcient information in the slice-select dimension such that under-sampling of the data in that direction results in aliasing. A less sharp cut-off can thus be observed when viewing the spatial frequencies in the slice-select (z) direction in Fourierencoded MRI. The existing aliasing in the slice-select direction provides the basis for using SR algorithms in enhancing the resolution. The illustration shown in Fig. 8 (taken from [3]) is used to validate the above claims: multislice 2-D image data sets were acquired, with half-voxel shifts in all three spatial directions. A 3-D iterative SR algorithm was applied [3]. The original LR image is shown (top left) with its original power spectrum (top right). The output of the SR process (double size in each dimension) is shown (bottom left) with its power spectrum (bottom right). The sharp frequency cut-off in the y (in-plane) direction is evident. A spreading out of the powerspectrum is present in the slice-select (z) direction, indicating an effective augmentation in the resolution. The conclusion regarding the dimensionality of the SR task is the following: the best that can be done in the in-plane (x, y) is to interpolate, via zero-padding, the given data to the desired resolution. In the slice-select dimension, sub-voxel spatial shifts can in fact be used to increase the resolution. In current Fourierencoded MRI systems, the task is inherently a 1-D, slice-select task. An interesting point is that if successful in this dimension, the goal of 3-D isotropy can in fact be achieved. 3.3. Experiments and results: anatomical MRI
In [3], the possibility of using SR for inter-slice MRI data was explored. Several key results are reviewed herein. The SR algorithm used was the Irani Peleg IBP method of [24] (Section 2). Anatomical MRI results are shown on a phantom, on inanimate objects and on a human brain. Qualitative results are shown, followed by quantitative evaluation. All imaging was performed with an RF head coil on either a 1.5 Tesla GE Signa MRI system or a 3 Tesla GE MRI
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FIGURE 9. SR on a phantom image. (a) The original LR data. (b) Zero-padding interpolation. (c) Interleaving the slices. (d) SR with box-PSF. (e) SR with Gaussian-PSF. Horizontal axis is the sliceselect axis [3].
system. The phantom used for the experiment consisted of long thin plastic partitions (teeth), lodged in a plastic block, placed 4 mm apart, surrounded by Gd-DTPA-doped water. The imaging sequence consisted of multislice fast spin-echo (FSE) with 16 slices, 3-mm thick, approximately parallel to the plastic partitions. Three sets of multislice data were acquired, with 1 mm shifts in the slice-select direction. The LR input voxel size was 1 1 3 mm3. Following the SR procedure, an output voxel is a 1 mm isotropic cube. Results are shown in Fig. 9. The visibility of the comb teeth has greatly improved by using SR rather than zero-padding interpolation. Moreover, more information is evident with SR than with interleaving. The implementation with a Gaussian PSF (e) seems to give slightly better results than when using a box-PSF (d): Better estimation of the HR image is achieved by using a blurring lter, h, that more closely matches with the MRI system and the MR image characteristics in the slice-select dimension. Results on an inanimate object are shown next. A papaya image (zoomed-in) is shown in Fig. 10. The x-axis is the sliceselect axis. The input LR image, shown in Fig. 10a, is of resolution 1 1 3 mm3, whereas the image following SR shown in Fig. 10b has a resolution of 1 1 1 mm3. To quantify the resolution augmentation, both the image and frequency domains are used. Figure 10c and d shows a
comparison of edges (two examples) within the two images, while Fig. 10e and f shows the augmentation of the frequency spectrum in the slice-select direction. Figure 11 shows initial SR results on human brain data. An FSE imaging sequence was used with three shifts in the slice direction. The original slice thickness was 4.5 mm, in-plane resolution was 1.5 mm and the number of slices was 22. SR output resolution was 1.5 mm (cubed). Results show a clear improvement in the progression from the LR input (Fig. 11a) or the zero-padded input (Fig. 11b) to the SR results (Fig. 11c and d). Quantitative evaluation was carried out on an apple input source (in [3] and revalidated in [4]). The resolution was quantied by the measurement of edge widths (see [3] for details on measuring width). Timing required and measured SNR were recorded as well. Table 1 summarizes the main results. Looking across the rows it is clear that the resolution in edgewidth improves as a shift is made from the zero-padded input to the HR source. The SR result is much better than the zeropadded or interleaved result, with the mean edge width of the SR result almost identical to the mean width of the HR source. SNR values decrease with the increased resolution. Note that the SNR of the SR result is higher than the SNR of 2-D thin slice acquisitions. In an MRI process, the goal is to obtain HR images with a high-SNR efciency, which is the ratio between the SNR of the result and the square root of the time length of the data acquisition sequence. The SNR efciency measure displays a similar trend: an SNR efciency of 7.63 is achieved for the SR result, compared with 6.13 for the HR acquisition.
3.4.
Experiments and results: fMRI
Peeters et al. [4] propose an optimization approach for HR fMRI reconstruction using SR. The fMRI acquisition is adapted to acquire two image stacks with low slice resolution, shifted over half-a-slice thickness. Two separate slice-shifted overlapping volumes are acquired, each obtained at half the acquisition time of the HR volume. The shifted volumes are combined via SR to reconstruct a stack of slices with half the acquisition thickness. The SR methodology used in this work is based on edge-preserving approaches and convergence rate studies [29]. fMRI data differs from anatomical MRI data in that it involves dynamical data; it images the hemodynamic response function (hrf). It is important to note that the image data acquired during the initial and nal portion of the hrf is not in a stationary state (plateau), and thus cannot be utilized in SR algorithms, which assume a combination of two sets of volumes acquired with an identical neurophysiological response condition. In [4], the solution suggested to this dynamics issue is the elimination of specic volumes that were acquired during the non-stationary state of the response.
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FIGURE 10. Papaya example. (a) LR data. (b) SR result. (c) and (d) Comparison between two corresponding edges of the input image (dotted line) and the SR image (solid line). (e) Power spectrum of input image. (f) Power spectrum of SR image.
Results of using SR on fMRI datasets, both simulated and real data are shown next, based on [4]. In the real fMRI datasets, a visual stimulation paradigm for retinotopic mapping was used. The stimuli used were designed to stimulate the horizontal (HM) and vertical (VM) visual eld meridian, using horizontally and vertically oriented wedgeshaped checkerboards alternating at 4 Hz. The HM and VM
stimuli were alternated in blocks of 10 brain volume scans. In this experiment, a total of 10 sessions of 12 blocks each, i.e. 120 scans per session, were performed on the same subject. During the experiment two different acquisition strategies were interleaved: the HR fMRI (ground truth) acquisition protocol and the LR (slice shifted) fMRI acquisition protocol, yielding ve high resolution (ground truth) and
FIGURE 11. Human brain MRI. (a) The original LR data. (b) Zero-padding interpolation. (c) SR with box-PSF. (d) SR with Gaussian-PSF [3].
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TABLE 1. Quantitative measures of SNR and resolution on apple FSE sequence MRI on an apple input source Zero-padded reconstruction Interleaved reconstruction SR reconstruction box PSF SR reconstruction Gaussian PSF High resolution Acquisition time (min:s) 1:28 4:24 4:24 4:24 4:00 SNR SNR Mean efciency edge width (pixels) (s21/2) 3.7 3.7 2.9 2.2 2.3 287 276 170 124 95 30.6 16.97 10.46 7.63 6.13
Original slice width of 4.5 mm; three shifts.
ve slice-shifted LR volume datasets. In the slice-shifted mode, the slice thickness was doubled as compared to the standard sequence. The two shifted volumes were acquired consecutively, with the second volume shifted in a slice position over a distance equal to the slice thickness of the HR images. The high-resolution data were collected on a Siemens Sonata 1.5 Tesla MR system. A matrix of 128 128 was acquired. Voxel size was taken as 2 2 2 mm3 for the ground-truth (HR) images and 2 2 4 mm3 for the slice-shifted images. The global acquisition time of the highresolution volume was 3328 ms and each of the slice-shifted interleaved volumes was 1664 ms (for additional acquisition protocol details see [4]). Figure 12 shows statistical parametric mapping (SPM) activation maps [30], displaying the activated areas above a statistical threshold (pcorr , 0.05), overlaid on the mean EPI slices of the interpolated datasets. Patches of color on the MRI brain slice shows differences in brain activity, with the colors representing the location of voxels that have shown statistically signicant differences between experimental conditions (see Appendix A). Figure 12a displays the images of the retinotopic mapping fMRI experiment in the acquisition plane with the corresponding activation superposed, and Fig. 12b shows activation images perpendicular to the slice direction. Cases compared include the following (top to bottom, left to right): original HR and LR inputs, an average dataset in which each HR voxel is computed as the average of all LR voxels that contain it (equivalent to the initial guess step of Irani Peleg), two SR results, and a composed result, which is equivalent to interleaving. In the SR algorithm, the regularization term was applied in all three dimensions (Anisotropic 3-D) or in the slice-select only (Anisotropic 1-D). Qualitative analysis of the results indicates overall similarity between the interpolated datasets and the reference HR dataset. A closer look at the data reveals that the 1-D and 3-D anisotropic SR datasets show higher t values at the foci of the activated areas than the reference HR, the original
LR and the average and composed data sets. Also the size of the activated clusters with a t value above threshold appears to be larger in the SR datasets compared to the original data. When comparing the two different SR datasets (3-D versus 1-D anisotropic regularization), the following differences are observed: the 3-D anisotropic images display more intense but less sharp activation patches than the 1-D anisotropic interpolated and HR dataset both in- and through-plane. The 1-D anisotropic SR dataset demonstrates a higher resolution of the activated patches in the slice direction than the LR dataset and the 3-D SR anisotropic dataset. These results can be explained via the larger smoothing inherent to the 3-D anisotropic interpolation algorithm in all directions. A second synthetic database was generated with known activation areas inserted, as shown in Fig. 13. The mean EPI MR volume was used as a template with a base resolution of 3 3 4 mm3. This template was duplicated 120 times to generate a dynamic time series, with different activated regions inserted in an interleaved mode of 10 rest volumes and 10 activated volumes. These activation regions consisted of different spheres with different radii and an irregularly shaped area at carefully chosen positions. The intensity of activation was set to a maximum of 8% peak signal change. Two slice-shifted LR datasets were generated by addition of the adjacent slices of the HR dataset. Gaussian noise was inserted with a standard deviation of 2% for the HR set and 1% for the LR volumes. Figure 13 shows the statistical analysis on the synthetic dataset, with similar conclusions obtained as in the real dataset. Both 1-D and 3-D SR anisotropic datasets extract the activated areas in good agreement with the position and size of the simulated activated areas. Quantitative measures of the ability to separate two close-by-activated areas were extracted. Figure 14 shows the line graphs of calculated t-values of a cut in the slice direction through two activated regions, with a separation of two slices in Fig. 14a and a single slice in Fig. 14b. The results demonstrate that the SR algorithms show a good separation, closely resembling the HR dataset and much better that in the LR input and average or interleaved datasets.
4.
SR IN PET
In this section, we focus on the application of SR to PET. We discuss the resolution limitations in PET and the challenges for SR in PET. Recent works that have started to investigate the potential of SR in this domain are reviewed herein. PET resolution is limited by physical properties, such as scatter, counting statistics, positron range and patient motion, as well as by the detector array geometry and the implemented acquisition protocol. Detector widths are limited to a certain minimal size, due to SNR considerations. A width that is too small will reduce detection efciency and will increase intercrystal scatter and penetration. Resolution in
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FIGURE 12. Slices of activated areas resulting from the visual stimulation paradigm overlaid on mean EPI images for different datasets. (a) Transversal acquisition plane. (b) Sagittal slices [4].
PET scanners is often degraded in order to achieve an acceptable image variance, where the variance is largely determined by the number of counts (counting statistics) collected during a scan. The noise that affects the counting statistics is comprised of several factors, as illustrated in Fig. 15. The rst one is the angular uncertainty of the photons created in the annihilation process. Although the photons emitted in this process should move in a straight line of 1808 with respect to each other, there is a small angular divergence. The second limiting factor is the scatter events that one or both of the photons may pass before they reach the detector. The scatter event causes miss-estimation of the line where the annihilation process took place. Also present are random events that occur simultaneously and introduce wrong information to the reconstructed image.
Current clinical PET scanners consist of 18 39 rings of detectors, which are aligned axially. A volumetric PET data set is commonly reconstructed by collecting a stack of 2-D transaxial images perpendicular to the axial (bed) direction. Many PET scanners have the option of restricting the line-of-response for gamma-ray coincident pair detection to the transverse plane perpendicular to the axial direction. This restrictive acquisition mode is termed the 2-D acquisition mode. A 3-D acquisition mode is one in which no restrictions apply during the acquisition process thus maximizing the number of events detected. In this scenario, the data are typically rebinned into transverse planes [32] and then reconstructed using a 2-D algorithm that generates images from projection data [33]. In either mode, a reconstructed 3-D PET data set consists of a stack of 2-D transverse images
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FIGURE 13. Comparison between activated areas observed in the high, low and interpolated datasets for the synthetic data. (a) Transversal plane. (b) Sagittal slices [4].
along an axial direction. Coronal or sagittal images are generated by re-sampling the voxel matrix along these planes. Accordingly, the spatial resolution in the transaxial plane is largely limited by the detector width, whereas the resolution along the axial direction is affected by the spacing of the detector rings. In practice, the nal reconstructed resolution of a PET image is usually poorer than the best obtainable, intrinsic resolution, because reconstruction algorithms typically trade-off resolution for reduced noise. In [16], an example is given where the intrinsic resolution is , 5 mm yet the nal resolution of the image is greater than 8 mm.
A typical resolution in clinical scanners is between 4 and 7 mm FWHM [31]. The SNR considerations, as briey outlined above result in an under-sampling of available data. Wider detectors dene a lower sampling frequency, while preserving a high-SNR ratio. This trade-off ensures that PET is a good candidate for SR. Higher resolution PET images may have several implications in research and clinical practice. The imaging of small cerebral structures such as the cortical sub-layers and nuclei may need PET spatial resolutions of , 2 mm [34, 35]. Higher PET resolution would also be benecial for improving
FIGURE 14. Line graphs of a cut in the slice direction showing the z-score for activated areas separated by two slices (a) and one slice (b) for different reconstructions. Real boundaries of the activated areas are shown with a solid black line (for color see [4]).
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H. GREENSPAN bed-shifts), combined axial and transaxial shifts, and a patient study for the detection of small lung lesions. In the 1-D mode, SR via Irani and Peleg [24] was implemented along the axial direction by combining the sets of four LR acquisitions, each shifted by one-fourth of a LR pixel relative to the previous one [similar method used in [3] for the anatomical MRI (Section 3)]. In a combination of 1-D (axial) and 2-D (transaxial) shifts, otherwise termed the 3-D brain acquisition mode, SR was applied to transverse images using rotation and translation in the transverse plane as the geometric shift between successive acquisitions. Small CT markers were attached to the phantom in order to track the shifts. In the patient study, CT images were evaluated to identify regions-of-interest exhibiting the suspicious small lung lesions. Following a PET/CT scan, the patient was requested to remain still and bed was positioned so that the ROI was centered in the FOV of the PET scanner. The scanner was programmed for four additional PET acquisitions of this FOV, lasting 4 min each. Between each acquisition, the bed was automatically shifted by 1 mm. The patient was not exposed to any additional radiation since the X-ray CT component of the PET/CT study was not repeated. Both standard and SR images were processed, with additional re-slicing to provide coronal, sagittal and transverse images through the lesion of interest. In all the scenarios above, the process of synthetically generating LR acquisitions, comparing them to the four measured acquisitions, and updating the HR estimate was repeated until a predened error was reached, or 16 iterations. The nal estimated HR image was referred to as the SR result. Figure 17 shows the 3-D brain acquisition mode in which both axial as well as transaxial shifts are conducted (combined 1-D and 2-D). CT markers provided the data needed to determine the geometric shifts between successive images. In this example, between the initial PET image (Fig. 17b) and the
FIGURE 15. PET events. (a) Graphic representation of true. (b) Scatter. (c) Random events [31].
sensitivity for detection of small tumors [36]. Cancer lesions need to be of diameters equal or larger than the resolution of the PET scanner to be identied provided they also have a high-glucose metabolism. Finally, higher resolution PET images may show a more differentiated anatomical structure. The increase in anatomical detail may aid in the registration of a PET image with a corresponding anatomical image from another modality, such as CT or MRI. In recent work, the possibility of augmenting PET resolution using SR algorithms was explored [5, 6]. In [5], the use of SR to improve PET resolution using shifts and rotations in the transaxial plane as well as along the axial direction was demonstrated (directions illustrated in Fig. 15). Motivated by the results of SR in MRI [3], the Irani Peleg SR algorithm was used, with results demonstrated on a phantom as well as initial patient data. In a phantom study, the SR technique was shown to improve resolution and increase the contrast ratio, using a commercially available PET scanner, without increasing total scan time. In the patient study, an increase in scan time for one eld of view (FOV) demonstrated that it is feasible to apply SR axially in a clinical setting without increasing the radiation dosage and without the need for any modication to the PET scanner hardware.
4.1.
Experiments and results
In [5], an SR scheme based on the Irani Peleg iterative algorithm is proposed and experimentally conrmed to improve the resolution of PET. SR attenuation corrected PET scans of a phantom were obtained using the 2-D and 3-D acquisition modes of a clinical PET/CT scanner (Discovery-LS PET/CT scanner, GE Medical Systems). A special phantom was constructed as shown in Fig. 16. The phantom contained holes of sizes 1, 1.5, 2, 4, 6 and 8 mm in diameter. Several experimental scenarios were tested: 1-D axial shifts (equivalent to
FIGURE 16. Phantom disk for PET experimentations ([5], #2006 IEEE).
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TABLE 2. Contrast ratio C for the PET signals in 3-D AC brain mode acquisition phantom trials ([5] #2006 IEEE) Image type Coronal No SR Four acquisitions interleaved SR Transaxial No SR SR
a
3-mm holes N/Ra 1.1 1.1 N/R 1.2
4-mm holes N/R 1.3 1.5 1.2 1.8
6-mm holes 2.1 2.4 2.8 2.2 3.2
8-mm holes 2.9 3.0 3.5 2.7 3.8

N/R, not resolved.
FIGURE 17. 3-D brain mode acquisition. (a) CT with transaxial rotation and translation, four acquisitions, gray arrow indicates one of the CT markers. (b) Initial transaxial PET image. (c) Fourth PET image ([5], #2006 IEEE).
fourth PET image (Fig. 17c), there is a rotation of 7.28 and a translation of 9.4 mm. Reconstructed images are shown in Fig. 18. The top two images are coronal images and the bottom two images are transaxial images. On the left are images generated using a standard PET acquisition and on
the right are SR images. All images were taken with the same total acquisition time. Both 4 (gray arrow) and 3 mm (black arrow) holes are more distinct in the SR images than in the standard acquisition images, for both coronary as well as the transaxial cases. Table 2 indicates that the SR image consistently provides a better contrast ratio than the other methods (see denition of Contrast in Section 2). An additional computational measure is the PSF FWHM, which can be computed from an approximate point source. Table 3 shows the case of a 1-mm diameter circular hole. The axial resolution in the 2-D whole-body mode was calculated to be 4.1 mm FWHM with the SR algorithm, which is superior to both interleaving (4.9 mm FWHM) and the standard reconstruction (4.8 8.6 mm FWHM). Thus, it can be concluded, that for the 3-D brain scenario, SR provides better resolution than the other methods both axially and transaxially. Figure 19 shows the SR data in a study of a patient with a suspicious small lung lesion on CT. The uptake in the small lesion seen in the SR image of Fig. 19c is more localized than that seen on the corresponding standard original PET image in Fig. 19b. The second uptake (gray arrow) does not appear clearly in the SR image of Fig. 19c; rather it falls in an adjacent image plane, shown in Fig. 19d.
TABLE 3. PSF FWHM values for phantom trials ([5] #2006 IEEE) Acquisition mode 2-D 3-D 3-D 3-D
a
Axis
Standard (mm) 4.8 to 5.3 to 5.2 to 4.9 to 8.6a 8.7 5.5 5.2
Interleave SR (mm) (mm) 4.1 4.8 4.3 4.3
FIGURE 18. 3-D brain mode acquisitionresults. (a) Standard coronal PET image. (b) Coronal image with SR. (c) Standard transaxial PET image. (d) Transaxial with SR ([5], #2006 IEEE).
whole body Axial brain Axial brain Radial brain Tangential
N/Ab N/A
Point source either centered in a pixel (lower value) or between two pixels (upper value). b N/A, not applicable.
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FIGURE 19. Coronal (left), sagittal (middle) and transaxial (right) sections of one FOV of a patient. The white arrows and black arrows denote the lesion of interest. (a) X-ray CT scan. (b) Original non-AC 18FFDG PET image using clinical reconstruction protocols. Image planes displayed are 4-mm thick. (c) Non-AC PET image through the center of the lesion of interest using SR. (d) Non-AC PET image using SR. The secondary foci of uptake (gray arrows) seen in the original images (b) are evident here, in super-resolution images of planes adjacent to those depicted in (c) ([5], #2006 IEEE).
5. SUMMARY AND CHALLENGES AHEAD Recent studies using SR in medical applications have demonstrated that using SR technology enables the limits on slice thickness as posed by the physical properties of existing imaging hardware to be effectively broken. Higher resolution in the image plane usually means acquisition with a smaller sampling distance, by using a smaller detector (e.g. in PET) or by using higher magnetic eld scanners and shorter sampling distances (in MRI). Due to physical constraints, HR image acquisition results in a lower SNR, i.e. a trade-off exists between resolution and SNR. One of the key features in SR technology is the ability to obtain an HR image with almost the same SNR as the original LR images from which it is constructed. In the current overview, we have demonstrated this fact for MRI, fMRI and PET. In both MRI and fMRI, reconstructed SR images displayed a close resemblance to the HR data, while improving the SNR. Two different SR algorithms were used in the reviewed study: the Irani Peleg iterative BP algorithm [2, 3, 5] and a minimization algorithm with a constraint term on the smoothness of the solution [4]. Overall, the two approaches display a similar set of results and conclusions. In the anisotropic SR
technique of [4], an investigation was conducted into the effect of 1-D versus 3-D smoothing. Quantitative comparison of the activation maps indicates that the 3-D anisotropic diffusion SR data set provides the largest response and the largest activated areas, with the extracted regions much smoother than the 1-D case. Thus, for increasing the detection capability of small-activated areas, a 1-D smoothing lter is to be chosen. In the PET phantom study [5], smaller features were resolved with SR than without (3-mm features, as opposed to the minimum of 4-mm in standard techniques), furthermore the features that were resolved have a higher SNR. The phantom trials showed improvement in both the axial and transaxial resolutions. The axial resolution was improved by 9 52% compared to the standard method and by 14 16% compared to the interleaving reconstruction method. In the 3-D brain mode transaxial images, SR improved the resolution by 12%. In the patient study, SR displayed more accurate (more localized) 18F-FDG uptake, without using any hardware changes or any increase in the patient radiation exposure. In a recently published study [6], two main extensions were investigated: rst, a more accurate SR algorithm was dened, in which both the blur kernel as well as the BP kernel are
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modeled with a Gaussian PSF. This, more accurate modeling, improves the above phantom results by an additional 2 4%. A second contribution of [6] is the fusion of PET and CT data: in addition to augmenting the PET resolution via SR, a post-processing step combines smoothing and edgeenhancement of the resultant image, based on the HR border information from the CT. The combined SR and anatomical edge information were evaluated in phantom and patient studies using a clinical PET scanner. In both cases, a substantial increase in contrast was demonstrated. SR, for images and image sequences, has customarily been treated as a 2-D problem. In the overviewed studies, SR has often been applied to 1-D signals. In the general medical arena, the extension of the SR concept to 3-D is strongly motivated, as has been recently proposed in [3]. Practical constraints have so far limited actual usage of true 3-D SR algorithms. In Fourier-encoded MRI, in-plane resolution is constrained (Section 3). The 3-D problem is thus downgraded to a 1-D task. It may be the case that with the new MRI technology that is not Fourier-based, the possibility for 3-D SR may arise. The PET SR example demonstrates SR in more than a single dimension. It seems that true 3-D may be applicable in this domain and may be a worthwhile effort for the future. Regardless of the dimensionality of the task, an important contribution of SR is the reduction of PVEs in the reconstructed image. In this respect, even if a SR algorithm is applied in a single (axial) dimension, it in effect contributes to the increased resolution in additional (transaxial) dimensions as well. 5.1. Spiral CT: a case where SR does not work?
the main obstacle for achieving increased resolution is the relatively large PSF of the system. To summarize, in spiral CT, a 3-D volume can be generated which is over-sampled (by decreasing the spiral pitchthe density of the helicon turns) and is heavily blurred across all dimensions. Various de-blurring algorithms can be utilized in this scenario. These in turn will not provide the sub-pixel level resolution desired. It is de-blurring, and not SR. 5.2. Additional issues and future challenges
An important question to address is the applicability of SR to a given medical imaging system. It is important to note that SR can augment the resolution as acquired by the system detectors, in cases in which the detectors have under-sampled the input data. In other words, high frequencies exist in the signal that reaches the detectors, and the detectors sampling limit leads to aliasing and degradation in the high-spatial frequency content, as output in the reconstructed image. SR reconstructs the aliased high frequency information thus providing a higher resolution output and minimizing the aliasing problem. In cases in which no frequencies exist that are higher than half of the detectors sampling frequency, no additional improvements in the image resolution can be obtained by SR technology. Such is the case in recently developed spiral CT systems. Today it is possible to scan the complete body trunk with submillimeter isotropic resolution in less than 30 seconds, with an effective slice thickness of 0.1 0.2 mm. Although the detectors sampling looks very promising, it is difcult to achieve this resolution in the reconstructed image. The main reason is the PSF of the spiral CT acquisition system, which has an equivalent bandwidth of 1 2 mm (for an elaborate discussion on the PSF of the CT system, see [37]). Thus, in spiral CT,
Newly emerging hardware may provide additional means for resolution augmentation. In the MRI eld, new parallel imaging techniques are currently being developed. Such techniques will allow faster acquisition and higher in-plane resolution. Yet, in many of the developed techniques, the added resolution comes at the expense of SNR. The ability to use SR post-processing of thick slices may provide the boost needed for the SNR. Novel encoding methodologies, such as non-Fourier methods (e.g. hadamard wavelets) are starting to emerge in MRI for encoding the third dimension [38]. Such technologies may enable the utilization of true 3-D SR techniques. The current overview was aimed at summarizing the key published results of SR in medical applications. As such, not all specic details per modality were presented, including certain pre-processing and post-processing steps. The reader is advised to consult the related literature for more specic implementation details. The overview is denitely not exhaustive: additional studies are currently emerging in the MRI research community [39, 40]. Additional modalities exist that have not been covered, including ultrasound and microscopy. Finally, the review is based on the published research and does not reveal the state-of-the-art in existing medical hardware. Future work can advance the topic in two main directions: On the clinical frontnding the applications that may gain most from the SR technology and implementing the theory in the clinical practice. On the SR algorithmic frontextending the investigation into additional medical imaging modalities as well as comparing between SR algorithms to nd the advantages of each per modality. A small number of studies have recently attempted to compare the performance of SR algorithms on MRI data. Results seem to indicate that no major difference exists between the Irani Peleg results and the ML-based frameworks. 5.3. SR versus segmentation versus registration
SR cannot be viewed as an isolated domain. A strong threeway relationship exists between SR, image segmentation and image registration. It is our conjecture that future research in the eld will focus on strengthening this three-way relationship. Augmented resolution of an image can augment its registration to another image or to an atlas, and it can, of course,
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[2] Peled, S. and Yeshurun, Y. (2001) Superresolution in MRI: application to human white matter ber tract visualization by diffusion tensor imaging. Magn. Reson. Med., 45, 29 35. [3] Greenspan, H., Oz, G., Kiryati, N. and Peled, S. (2002) MRI inter-slice reconstruction using super-resolution. Magn. Reson. Imaging, 20, 437446. [4] Peeters, R.R. et al. (2004) The use of super-resolution techniques to reduce slice thickness in functional MRI. Int. J. Imaging Syst. Technol., 14, 131 138. [5] Kennedy, J.A. et al. (2006) Super resolution in PET imaging. IEEE Trans. Med. Imaging, 25, 137147. [6] Kennedy, A., Israel, O., Frenkel, A., Bar-Shalom, R. and Azhari, H. (2007) Improved image fusion in PET/CT using hybrid image reconstruction and super-resolution. Int. J. Biomed. Imaging, Article ID 46846. [7] Beutel, J., Kundel, H.L. and Van Metter, R.L. (2000) Handbook of Medical Imaging. SPIE Press, Bellingham. [8] Cho, Z.H., Jones, J.P. and Singh, M. (1993) Foundations of Medical Imaging. Wiley-Interscience, New York. [9] Liang, Z.P. and Lauterbur, P.C. (2000) Principles of Magnetic Resonance Imaging. IEEE Press. [10] Epstein, C.L. (2003) Mathematics of Medical Imaging. Prentice Hall, Upper-Saddle River, NJ. [11] Gambhir, S.S. et al. (2001) A tabulated summary of the FDG PET literature. J. Nucl. Med., 42, 1S 93S. [12] Moretti, A., Gorini, A. and Villa, F. (2003) Affective disorders, antidepressant drugs and brain metabolism. Mol. Psychiatry, 8, 773 785. [13] Matsunari, I. et al. (2001) Phantom studies for estimation of detect size on cardiac 18F SPECT and PET: implications for myocardial viability assessment. J. Nucl. Med., 42, 15791585. [14] Bax, J.J. et al. (2000) 18-Fluorodeoxyglucose imaging with positron emission tomography and single photon emission computed tomography: cardiac application. Semin. Nucl. Med., 30, 281298. [15] Bengel, F.M. et al. (2000) Non-invasive estimation of myocardial efciency using positron emission tomography and carbon-11 acetate-comparison between the normal and failing human heart. Eur. J. Nucl. Med., 27, 319326. [16] Ollinger, J.M. and Fessler, J.A. (1997) Positron-emission tomography. IEEE Signal Process. Mag., 14, 43 55. [17] BrainWeb. http://www.bic.mni.mcgill.ca/brainweb/ [18] Park, S.C., Park, M.K. and Kang, M.G. (2003) Super-resolution image reconstruction: a technical overview. IEEE Signal Process. Mag., 20, 2135. [19] Tsai, R.Y. and Huang, T.S. (1984) Multiframe Image Restoration and Registration. Advances in Computer Vision and Image Processing, pp. 317339. JAI Press Inc., Greenwich, CT. [20] Kim, S.P., Bose, N.K. and Valenzuela, H.M. (1990) Recursive reconstruction of high resolution image from noisy undersampled multiframes. IEEE Trans. Acoust. Speech, 38, 10131027. [21] Ur, H. and Gross, D. (1992) Improved resolution from subpixel shifted pictures. Comput. Vis. Graph. Model. Image Process., 54, 181186.
greatly contribute to its segmentation (e.g. resolving PVE). We would like to suggest that registration and segmentation are also critical contributors in advancing the SR eld, in general, and in particular in the medical domain. Accurate registration is a key factor in achieving satisfactory SR results and is required to facilitate the use of SR algorithms in real-world clinical settings. In the studies presented, patient motion was largely ignored. In both MRI as well as PET, the focus was on head scans, given that the head is constrained to a cradle and is less likely to move during the scan. For the more general case of a moving subject or organ, accurate image registration methods need to be incorporated. Strong registration schemes will enable the development of true 3-dimensional algorithms that involve 3D patient motion. Image segmentation and image modeling can advance the eld by introducing important prior knowledge, which in turn can be included as part of the regularization terms within the SR formalism. Bi-lateral total variation regularization was shown to provide a within-region smoothing effect while preserving strong transitions (edges) within the image. A variation on this theme was demonstrated as a post-processing step in [6] with improved results. Utilizing image segmentation further may entail using region, or tissue properties (such as characteristic intensity), as key information within the regularization framework. Important information exists in the medical domain, such as statistical atlases for location prior, and tissue modeling for intensity priors, all of which provide additional key information and opportunities for advanced SR algorithms in medical applications.
ACKNOWLEDGEMENTS I would like to thank my colleagues and collaborators on SR related research: Dr. Sharon Peled, Prof. Nahum Kiryati, and Dr. Yossi Rubner. Thanks to Prof. Azhari and Dr Kennedy for discussions on SR in PET applications. Supporting the current study: Uri Marias, Oren Friefeld, Avi Ben-Ezra. The author is grateful for the suggestions by the anonymous referees to this study.
FUNDING Research was supported in part by the Ela Kodesz Institute for Medical Engineering and Physical Sciences, and by the Adams Super-Center for Brain Studies, Tel-Aviv University. REFERENCES
[1] Roux, C. and Udupa, K. (2003) Special issue on emerging medical imaging technology. Proc. IEEE, 91, 14791482.
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MEDICAL IMAGING APPENDIX A: A BRIEF INTRODUCTION TO MEDICAL IMAGING MODALITIES A.1. Magnetic resonance imaging
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[22] Elad, M. and Hel-Or, Y. (2001) A fast super-resolution reconstruction algorithm for pure translational motion and common space invariant blur. IEEE Trans. Image Process., 10, 11871193. [23] Chiang, M.C. and Boult, T.E. (2000) Efcient super-resolution via image warping. Image Vis. Comput., 18, 761771. [24] Irani, M. and Peleg, S. (1993) Motion analysis for image enhancement: resolution, occlusion, and transparency. J. Vis. Commun. Image Represent, 4, 324 335. [25] Patti, A.J., Sezan, M.I. and Tekalp, A.M. (1994) High-resolution image reconstruction from a low-resolution image sequence in the presence of time-varying motion blur. Proc. ICIP, Austin, TX, pp. 343 347. [26] Elad, M. and Feuer, A. (1997) Restoration of single super-resolution image from several blurred, noisy and down-sampled measured images. IEEE Trans. Image Process., 6, 1646 1658. [27] Farsiu, S., Robinson, M.D., Elad, M. and Milanfar, P. (2004) Fast and robust multiframe super resolution. IEEE Trans. Image Process., 13, 13271344. [28] Schefer, K. (2002) Superresolution in MRI? Magn. Reson. Med., 48, 408. [29] Nikolova, M. and Ng, M. (2001) Fast image reconstruction algorithms combining half-quadratic-regularization and preconditioning. Proc. ICIP, Thessaloniki, Greece, pp. 277 280. [30] Statistical Parametric Mapping (SPM). Available at http://www. l.ion.ucl.ac.uk/spm/ [31] Tarantola, G., Zito, F. and Geundini, P. (2003) PET implementation and reconstruction algorithms in whole-body applications. J. Nucl. Med., 44, 756769. [32] Defrise, M. et al. (1997) Exact and approximate rebinning algorithms for 3-D PET data. IEEE Trans. Med. Imaging, 16, 145 148. [33] Hudson, H.M. and Larkin, R.S. (1994) Accelerated image reconstruction using ordered subsets of projection data. IEEE Trans. Med. Imaging, 13, 601 609. [34] Kessler, R.M. (2003) Imaging methods for evaluating brain function in man. Neurobiol. Aging, 24, S21S35. [35] Shmand, M. et al. (1998) Performance results of a new DOI detector block for a high resolution PET-LSO research tomography HRRT. IEEE Trans. Nucl. Sci., 45, 30003006. [36] Fukui, M.B., Blodgett, T.M. and Meltzer, C.C. (2003) PET/CT imaging in recurrent head and neck cancer. Semin. Ultrasound CT MR, 24, 157 163. [37] Schwarzband, G. and Kiryati, N. (2005) The point spread function of spiral CT. Phys. Med. Biol., 50, 53075322. [38] Goelman, G. (2000) Fast 3D T2 weighted MRI with Hadamard encoding in the slice select direction. Magn Reson Imag., 18, 939 945. [39] Carmi, E. et al. (2006) Resolution enhancement in MRI. Magn. Reson. Imaging, 24, 133 154. [40] Hsu, J.T. et al. (2004) Application of wavelet-based POCS superresolution for cardiocascular MRI image enhancement. Proc. 3rd ICIG, IEEE, pp. 572575.
MRI utilizes the principles of nuclear magnetic resonance, a spectroscopic technique used to obtain microscopic chemical and physical information about molecules containing atomic nuclei posessing non-zero magnetic moment, or spin. The hydrogen nucleus in water is the most common nucleus used for MRI. Placed in a magnetic eld, the particles spin can absorb external energy in the form of a photon, and thus move to an energy level higher than the original equilibrium energy level. Once the external magnetic eld is stopped, the spins start moving back to the lower energy level. The shift between energy states results in an amount of energy that is emitted from the system and which can be detected using wire coils. The measured induced current in the coils is called free induction decay (FID) signal. The magnitude of the signal is proportional to the density of the protons in the specimen. The MR image is formed by extracting the locations of the different spins from the FID signals. By using a magnetic eld, which varies spatially (e.g. changes linearly in all three directions), spins in different locations will yield FID signals with different frequencies. Frequency encoding then enables to extract the spatial information. In three dimensions, a plane can be dened by slice selection, in which an RF pulse of dened bandwidth is applied in the presence of a magnetic eld gradient in order to reduce spatial encoding to two dimensions. Spatial encoding can then be applied in 2-D after slice selection, or in 3-D without slice selection. In either case, a 2-D or 3-D matrix of spatially encoded phases is acquired, and these data represent the spatial frequencies of the image object. Images can be created from the acquired data using the discrete Fourier transform. In conventional 2-D multi-slice MR imaging, the RF pulse rst selects the 2-D slice to be analyzed, following which a combination of frequency encoding of the signal in one direction and phase encoding in the other direction enables to encode the 2-D spatial information within the slice (so called in-plane). A single slice may require multiple RF excitations, with predened repetition time (TR) in order to be fully encoded. The MR image intensities (per voxel) are proportional to the number of nuclei in each voxel. MR image contrast is determined by several time constants, each of which reects a certain relaxation process that establishes equilibrium following the RF excitation. As the high-energy nuclei relax and realign, they emit energy at rates which are recorded to provide information about their environment. The realignment of nuclear spins with the magnetic eld is termed longitudinal relaxation and the time required for a certain percentage of the tissue nuclei to realign (typically about 1 s for tissue water) is termed Time 1 or T1 (spin-lattice relaxation). T2-weighted
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H. GREENSPAN image intensity varies whenever the spatial direction of the diffusion gradient is changed. Models have been proposed to account for such changes, such as the diffusion tensor model. A.1.3. Diffusion tensor imaging DTI provides a unique tool for visualization of the direction and intactness of white matter ber tracts in vivo by identifying the preferred direction of diffusion. Axons in the brain are structured in parallel bundles and generally have a myelin sheath that preferentially facilitates the diffusion of water molecules along their main direction. If we apply diffusion gradients (i.e. magnetic eld variations in the MRI magnet) in at least 6 directions, it is possible to calculate, for each voxel, a tensor (a 3*3 matrix) that describes this diffusion anisotropy. The ber direction is indicated by the tensor s main eigenvector. An example image is shown in Figure 3(d) where the brightness is weighted by the tracts anisotropy. HR DTI, combined with algorithms for tracing bers in three-dimensions in tensor elds, has the potential to enable ber tract mapping of critical functional pathways in the brain. A.1.4. Functional MRI fMRI is the use of MRI to measure the hemodynamic response related to neural activity in the brain or spinal cord of humans or other animals. During brain activity, there is a rapid momentary increase in the blood ow to the specic thought center in the brain. For example, when moving a nger there is a rapid momentary increase in the circulation of the specic part of the brain controlling the nger movement. The increase in circulation means a decrease in deoxyhemoglobin, which is paramagnetic and affects mainly the T2* of the local brain tissue. The difference in T2* relative to surrounding tissue causes a contrast between the tissues, referred to as blood oxygenation level-dependent (BOLD) contrast. Higher BOLD signal intensities arise from decreases in the concentration of deoxygenated hemoglobin since the blood magnetic susceptibility now more closely matches the tissue magnetic susceptibility. By collecting data in an MRI scanner with parameters sensitive to changes in magnetic susceptibility one can assess changes in BOLD contrast. BOLD effects are measured using rapid volumetric acquisition of images (mostly with T2*weighted acquisition). Such images can be acquired with temporal resolution of 1 4 s. Voxels in the resulting image typically represent cubes of tissue 2 4 mm on each side in humans. fMRI data provide a time series of samples for each voxel in the scanned volume. A variety of methods are used to correlate these voxel time series with an assigned task in order to produce maps of task-dependent activation. A well-known statistical analysis package is the SPM [30]. This is a statistical technique for examining differences in brain activity recorded during functional neuroimaging experiments. Following the analysis, differences in brain activity are often shown as patches of color on an MRI brain slice, with the colors
imaging relies upon local dephasing of spins in the transverse plane; the transverse relaxation time (typically , 100 ms for tissue water) is termed Time 2 or T2 (spin-spin relaxation). T2 imaging employs a spin echo technique in which spins are refocused to compensate for local magnetic eld inhomogeneities. A subtle but important variant of the T2 technique is called T2* imaging, which is performed without the refocusing. This sacrices some image integrity in order to provide additional sensitivity to relaxation processes that cause incoherence of transverse magnetization. Conventional image contrast is created by using a selection of image acquisition parameters that weights the signal by T1, T2 or T2*, or no relaxation time (proton-density images). In the brain, T1-weighting causes ber tracts (nerve connections) to appear white, congregations of neurons to appear gray and cerebrospinal uid to appear dark. The contrast of white matter, gray matter and cerebrospinal uid is reversed using T2 or T2* imaging, whereas proton-weighted imaging provides less contrast in normal subjects. Various MRI sequences exist, each dened by a set of sequence parameters that determine the selected compromised between contrast, spatial resolution and speed. Among the frequently used MRI sequences are fast spin echo (FSE) and echo planar imaging (EPI). The essential components for any imaging sequence include: An RF excitation pulse, required for the phenomenon of magnetic resonance, gradients for spatial encoding (2D or 3D), and a signal reading, that combines one or a number of echo types (e.g. spin echo, gradient echo) and determines the type of contrast (the varying inuence of relaxation times T1, T2 and T2*). A.1.1. MRI angiography Contrast enhanced angiography is based on the difference in the T1 relaxation time of blood and the surrounding tissue when a paramagnetic contrast agent is injected into the blood. This agent reduces the T1 relaxation times of the uid in the blood vessels relative to surrounding tissues. When the data are collected with a short TR value, the signal from the tissues surrounding the blood vessels is very small due to its long T1 and the short TR. Images of a region of interest are recorded with rapid volume imaging sequences. An example angiographic image is shown in Fig. 3c. A.1.2. Diffusion-weighted imaging DWI uses very fast scans with an additional series of gradients (diffusion gradients) rapidly turned on and off. Protons from water diffusing randomly within the brain, via Brownian motion, lose phase coherence, and thus signal during the application of the diffusion gradients. More precisely, given a spatial direction and a chosen amount of time during which water molecules are left free to diffuse, a sophisticated MRI scanner produces an image attenuated according to the magnitude of the diffusion. The more attenuated the image is at a given position, the more diffusion there is locally. The
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representing the location of voxels that have shown statistically signicant differences between conditions. The gradient of color is mapped to statistical values, such as t-values or z-scores, enabling to delineate the relative statistical strength of a given area of activation. An example fMRI image is shown in Fig. 3e and in color in Fig. 12. A.2. X-ray computed tomography (CT)
cross-sectional slices can be reconstructed at any z position, while in the planar CT they were limited to those positions where the circular scans had been performed. An example CT image is shown in Figure 6(a). At RSNA 2007, Philips announced a 256 slice scanner, while Toshiba announced a dynamic volume scanner based on 320 slices. A.3. Positron Emission Tomography (PET)
In conventional CT, the slices are acquired sequentially. The X-ray tube rotates around the subject and multiple circular acquisitions are extracted until a slice is acquired. Then, the bed (on which the subject lies) is moved forward incrementally. The size of the step determines the resolution in the longitudinal axis. During CT scanning, the cross-section is probed with X-rays from various directions and attenuated signals are recorded and converted to projections of the linear attenuation coefcient distribution of the crosssection. These X-ray shadows are directly related to the Fourier transform of the cross-section, and can be processed to reconstruct the cross-section. The CT scanner can image complete organs and volumes using a large series of twodimensional X-ray images taken around a single axis of rotation. Over recent years, a transition has been made from slice-by-slice imaging to volume imaging, with the introduction of spiral scan modes. The spiral (helical) X-ray CT refers to the modern CT scanning technique, in which the rotational movement of the X-ray source is combined with the simultaneous longitudinal movement of the patients bed, creating effectively a helical movement of the source around the patient. Spiral CT advanced conventional CT in speeding up the scanning process as well as in converting it to a true 3-D imaging modality. With spiral CT, the
The techniques used in nuclear medicine involve labeling of a chosen molecule with a radioactive atom and administrating a dose of the labeled molecules to the patient. The molecules follow their specic biochemical pathways inside the body. The atoms used as labels are unstable isotopes and undergo radioactive decay at random, leading to the emission of gamma-ray photons which can be detected outside the body. In PET, the label atoms decay by emitting a positron. Within a short distance, the positron combines with an electron to produce two gamma-ray photons (each of energy 511KeV) traveling in opposite directions along the same line (of random orientation). When the two photons are detected at the same time (short time window of 6 12 ns), the coordinates are recorded by the detector system, and the assumption is made that these photons originated from annihilation at some point along the line in space between the two detection points. An illustration of the PET acquisition is presented in Fig. 2b. The total number of coincidence events detected by a given pair of detectors constitutes a measure of the integrated radioactivity along the strip joining the two detectors (lineintegral projection data). Using the obtained data from a large number of detectors and different views, a 2-D map is formed from which a 2-D image is reconstructed. An example PET image is shown in Fig. 6b.

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Super-Resolution in Medical Imaging

THE COMPUTER JOURNAL, Vol. 52 No. 1, 2009

FIGURE 1. Illustration of the general medical imagery acquisition process.

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Resolution limitations and challenges in medical imaging

SR ALGORITHMS: BRIEF OVERVIEW

Can SR support the medical imaging challenges?

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48 2.1. Modeling the image acquisition process

The general formalism of SR

SR parameters and performance evaluation: general and medical domain considerations

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Experiments and results: fMRI

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Original slice width of 4.5 mm; three shifts.

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Experiments and results

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3-mm holes N/Ra 1.1 1.1 N/R 1.2

4-mm holes N/R 1.3 1.5 1.2 1.8

6-mm holes 2.1 2.4 2.8 2.2 3.2

8-mm holes 2.9 3.0 3.5 2.7 3.8

N/R, not resolved.

Interleave SR (mm) (mm) 4.1 4.8 4.3 4.3

whole body Axial brain Axial brain Radial brain Tangential

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