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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 specific activities and specified tasks. Each imaging system has a character-
istic 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

1. INTRODUCTION
The main goal of medical imaging is to extract a 3-D modeling
of the human body or specific 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 func-
tional information, e.g. revealing locations of activity within
the brain for specific activities and specified tasks. The
medical imaging field is rapidly evolving in increased resol-
ution machines and advanced content-processing tools [1].
Medical imaging system developers strive to increase resolu-
tion since higher resolution is the key to more accurate under-
standing 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 field-of-view [or point-of-view (POV)] of the HR
scene. A variety of reconstruction algorithms have been pro-
posed 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 prior-
knowledge 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 func-
tional 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 field has so far been in what can be defined
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 specific 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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 44
data. Real data scenarios introduce various artifacts that need
to be addressed, patient motion difficulties as well as acqui-
sition time constraints.
A comparison across several currently published SR var-
iants algorithmic variants does not reveal major differences.
Future major challenges in this field include: on the theor-
etical 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 define the con-
tribution of SR in the medical field.
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
field. A brief overview of the SR algorithms, SR parameteriza-
tion, 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 finalize this overview paper, in Section 5.
1.1. Medical imaging acquisition process and clinical
significance
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 radio-
active 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 specific imaging modality [e.g.
radio frequency (RF) coils in MRI, crystal detectors in PET].
Figure 2 presents a schematic description of an X-ray trans-
mission (a) and a photon emission process (b). Following
FIGURE 1. Illustration of the general medical imagery acquisition
process.
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H. GREENSPAN
the energy acquisition process, various algorithmic transform-
ations 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 briefly 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 set-
tings 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 rep-
resent three (2-D) slice directions, as displayed in the figure.
The defined 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 flowing blood in the arteries
and veins of the body, with intensity proportional to the velo-
city of the flow. 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 character-
istics of water diffusion. DWIs are very useful in diagnosing
vascular strokes in the brain and to study white matter dis-
eases. 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 fiber tracts in vivo by identifying
the preferred direction of diffusion. HR DTI combined with
algorithms for tracing fibers in three dimensions in tensor
fields has the potential to enable fiber tract mapping of critical
functional pathways in the brain. The clinical applications are
the tract-specific 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 neuro-
surgical planning. fMRI measures the changes in blood flow
 SR IN MEDICAL IMAGING 45

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 cross-
section 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) Angio-
graphy. (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 diag-
nosis of cerebrovascular accidents and intracranial hemorrhage;
facial and skull fractures evaluation; surgical planning for cra-
niofacial and dentofacial deformities; detecting acute and
chronic chest diseases; imaging of coronary arteries (cardiac
CT angiography); abdominal diseases; imaging complex frac-
tures 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 func-
tional 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 efficiency
[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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 46 H. GREENSPAN

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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 SR IN MEDICAL IMAGING 47

1.2. Resolution limitations and challenges in medical means for extending current medical imaging resolution
imaging limitations. The goal of SR algorithms is to improve the
image resolution in cases in which the image was under-
A common goal in all medical imaging systems is to increase
sampled. Such cases involve the following: first, the imaged
the resolution and, to the extent possible, achieve true isotro-
object has high-frequency content. Second, the sampling fre-
pic 3-D imaging. To capture the entire frequency content of
quency as defined by the detectors, does not fulfill the
the imaged object, a sampling rate at the Nyquist frequency
Nyquist frequency; thus, aliasing and degradation in the high-
is required, defined as twice the highest frequency present in
frequency content can be observed. The SR process helps
the imaged object. Correspondingly, the sampling distance
overcome the detector sampling limitations by practically
must be one-half the spatial resolution, defined as the distance
increasing the sampling rate, and thus utilizing additional
between half-value points of the system impulse response, or
high-frequency information and reducing the aliasing
the full-width-at-half-maximum (FWHM).
effects. Note that in cases in which no frequencies higher
In practice, the range of frequencies captured is limited by
than half of the detectors sampling frequency exist, SR will
the maximal sampling frequency of the imaging device detec-
in effect result in the averaging of noise; in such cases, no
tors, as defined by the detector pitch, or the detector spacing.
additional improvements in the image resolution can be
Reduced size (width) of detectors and smaller inter-detector
obtained by SR.
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 detec- 2. SR ALGORITHMS: BRIEF OVERVIEW
tors, which are in turn tuned to SNR and timing considerations
The term SR refers here to a technique in which several LR
in the system. Within each imaging modality, specific physical
images, from different POV relative to the image object, are
laws are in control, defining the meaning of noise and the sen-
combined to obtain a higher-resolution image. Several SR
sitivity of the imaging process. Signal processing rules govern
reconstruction methodologies have been developed in the
the system design in an attempt to achieve an acceptable com-
last two decades [18]. In initial works [e.g., 19], the frequency
promise between resolution and SNR. The resolution limit-
domain was used to demonstrate the ability to reconstruct one
ations in MRI and PET will be defined in depth in Sections
improved resolution image from several down-sampled noise-
3 and 4, respectively.
free versions of it, based on the spatial aliasing effect. The fre-
A resolution-related challenge in medical image processing
quency domain approach was further generalized to noisy and
is known as partial volume effect (PVE), which arises when an
blurred images in [20] and a spatial domain alternative was
interface between two different tissues occur within a single
suggested in [21]. Further non-iterative spatial domain data
voxel. The PVE is a direct consequence of limited resolution
fusion approaches were proposed in [22, 23].
during the acquisition process. In general, PVE blurs the
An iterative back-projection (IBP) method was proposed in
boundary between tissues and adds complexity to tissue
[24]. This method starts with an initial guess of the outcome
characterizations. In MRI, the resulting image pixels display
image, projects the initial result to simulate the LR measure-
a gray level proportional to the weighted average of the
ments, and updates the temporary guess according to the simu-
signals stemming from neighboring tissues. The exact location
lation error. Further detail on the IBP method is provided in
of boundaries may be shifted thus introducing a major obstacle
the following subsections.
for anatomical MRI brain segmentation. In a CT image, each
A set theoretic approach to SR was suggested in [25]. Here,
voxel represents the attenuation properties of a specific
convex sets are defined which represent tight constraints on
volume. When more than a single tissue is present within
the required image. Nonlinear constraints are combined
the voxel, the value will be some (nonlinear) average of the
within the restoration process and a projection onto convex
tissues’ attenuation properties. In DTI, where isotropic resolu-
sets (POCS) algorithm is utilized. A hybrid model that com-
tion is particularly important, PVEs are a limiting factor in the
bines maximum-likelihood (ML) and POCS was suggested
analysis of directional and structural axonal connectivity.
in [26]. More recent SR works aim at combining the SR
Increased resolution can help overcome or reduce the pro-
approaches with regularization terms, e.g. in [27] fast and
blems associated with PVE.
robust multi-frame SR is proposed using L1 norm minimiz-
ation and robust regularization based on a bilateral prior to
deal with different data and noise models.
1.3. Can SR support the medical imaging challenges?
In this section, we mathematically define the general image
SR reconstruction deals with combining several LR images to acquisition procedure, and present the general formalism for
create a HR image. SR techniques have been suggested in SR. It is our goal to provide the reader with a brief overview
recent years as a means for increasing resolution without alter- of specific algorithms and related parameterization issues, as
ing the existing imaging hardware. Thus, they can be seen as a related to the research works reviewed herein.

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 48
2.1. Modeling the image acquisition process
N thetically generated image are up-sampled to achieve the
Given a set fykgk¼1of LR images and assuming all LR images
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 deci-
mation, as in equation (1),
yk ¼ ð fk ðxÞhÞ # s þ vk ; k ¼ f1; . . . ; N g;
where fk is the kth geometrical transformation of the image x to
the same reference frame of acquisition for yk, h is a blur
kernel—often referred to as the point spread function (PSF),
defined 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 acqui-
sitions brought to the same reference point and up-sampled:
1X K
xð0Þ ¼ f 1 ðyk " sÞ;
k k¼1 k
where yk is one of K acquisitions, fk the geometric transform-
ation 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,
fỹ(n)
k g, can be extracted. The process involves shifting the HR
image to the kth POV, blurring to account for the psf and down-
sampling to the system’s sampling rate. The nth LR synthetically
sampled set of images fỹ(n)
k g is thus obtained from the nth
approximation of the HR image x (n) (ignoring the noise), by:
y~ ðnÞ ðnÞ
k ¼ ð fk ðx ÞhÞ # s:
The current iteration x (n) is updated according to the differ-
ence between the synthetically generated set of LR images
fỹ(n)
k g and the actual acquired set of LR images fykg:
1X K
xðnþ1Þ ¼ xðnÞ þ f 1 ðððyk  y~ ðnÞ
k Þ " sÞpÞ:
k k¼1 k
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H. GREENSPAN
The differences between the original image and the syn-
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 ¼ h). The defined iterative
process [equations (3) and (4)] is repeated until a predefined
error measure, such as the mean square error in the
maximum-likelihood (ML) sense:
K  2
X  ðnÞ 
12ML ðxÞ ¼ yk y~ k  ð5Þ
ð1Þ k¼1
has been minimized or has reached a predefined threshold. Alter-
natively, a maximum number of iterations has been reached.
Equation (1) defines 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 indepen-
dent 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 know-
ledge on the imaged data, or the desired reconstructed
solution, is incorporated as a regularization term in the mini-
mization process:
K 
X  2
 ðnÞ 
12MAP ðxðnÞ Þ ¼ yk y~ k  þlA xn ; ð6Þ
ð2Þ k¼1
where A(x) is the regularization term providing prior infor-
mation on the desired SR image x, and l is the regularization
coefficient 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 filter [27].
2.3. SR parameters and performance evaluation:
general and medical domain considerations
Each SR algorithm has certain key parameters that need to be
ð3Þ determined to most closely match with the true imaging
system characteristics and specific application scenario. Two
key parameters are the transformation and blur: the transform-
ation 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
ð4Þ (from an original position) between the object (patient bed)
and the imager.
 SR IN
The blur, h, is defined by the imaging system PSF. In
medical imaging systems, the PSF is often defined as the
slice excitation profile. Experiments indicate that the typical
slice profiles 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 first
is a rectangular pulse PSF which is a crude estimation for
the slice profile (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 Gaus-
sian 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 func-
tion h. For the typical slice profiles mentioned above, the p
filter 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 corre-
spondingly set to unity. In [6], an increase in model accuracy
is attempted by defining both the blur kernel as well as the BP
kernel, to be modeled as a Gaussian PSF.
In regularization-based schemes, an additional minimiz-
ation parameter exists per defined objective function. Optimi-
zation of this parameter can be performed in all three spatial
directions, denoted as ‘3-D anisotropic filtering’, or in the
slice select direction only, known as ‘1-D anisotropic
filtering’.
Quantitative measures for any image enhancement pro-
cedure 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 defines the ratio between the average
signals to the average background.
Traditional alternatives to SR reconstruction include zero-
padding, or sinc interpolation, and interleaving. In zero-
padding, 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 resol-
ution 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
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MEDICAL IMAGING 49
image inputs, to generate a single large image. In the studies
reviewed below, the two alternatives are utilized for compari-
son 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 method-
ologies 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 algori-
thms, 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 difficult 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 modi-
fied 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 res-
olution as well as spatial resolution is important. Most 3-D
acquisition procedures cannot reach the required temporal res-
olution 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
 50
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 recon-
structed 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 find 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 chal-
lenge is to achieve the HR outcome without decreasing the
SNR.
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, Fourier-
encoded 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 orig-
inal 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
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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].
sufficient 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 Fourier-
encoded MRI. The existing aliasing in the slice-select direc-
tion 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 power-
spectrum 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 Fourier-
encoded MRI systems, the task is inherently a 1-D, slice-select
task. An interesting point is that if successful in this dimen-
sion, 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. Quali-
tative 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
 SR IN
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 slice-
select 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 filter, 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 slice-
select axis. The input LR image, shown in Fig. 10a, is of res-
olution 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 fre-
quency domains are used. Figure 10c and d shows a
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MEDICAL IMAGING 51
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 quan-
tified 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 edge-
width improves as a shift is made from the zero-padded input
to the HR source. The SR result is much better than the zero-
padded 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 efficiency, 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 effi-
ciency measure displays a similar trend: an SNR efficiency
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 conver-
gence 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 final 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 specific volumes that
were acquired during the non-stationary state of the response.
 52 H. GREENSPAN

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 field
meridian, using horizontally and vertically oriented wedge-
shaped 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 strat-
egies were interleaved: the HR fMRI (ground truth) acqui-
sition protocol and the LR (slice shifted) fMRI acquisition
protocol, yielding five 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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 SR IN MEDICAL IMAGING 53

TABLE 1. Quantitative measures of SNR and resolution on apple LR and the average and composed data sets. Also the size of
FSE sequence the activated clusters with a t value above threshold appears
to be larger in the SR datasets compared to the original data.
MRI on an apple Acquisition Mean SNR SNR
input source time (min:s) edge width efficiency
When comparing the two different SR datasets (3-D versus
(pixels) (s21/2) 1-D anisotropic regularization), the following differences are
observed: the 3-D anisotropic images display more intense
Zero-padded 1:28 3.7 287 30.6 but less sharp activation patches than the 1-D anisotropic
reconstruction interpolated and HR dataset both in- and through-plane. The
Interleaved 4:24 3.7 276 16.97 1-D anisotropic SR dataset demonstrates a higher resolution
reconstruction of the activated patches in the slice direction than the LR
SR reconstruction 4:24 2.9 170 10.46 dataset and the 3-D SR anisotropic dataset. These results can
box PSF be explained via the larger smoothing inherent to the 3-D ani-
SR reconstruction 4:24 2.2 124 7.63 sotropic interpolation algorithm in all directions.
Gaussian PSF A second synthetic database was generated with known acti-
High resolution 4:00 2.3 95 6.13 vation areas inserted, as shown in Fig. 13. The mean EPI MR
Original slice width of 4.5 mm; three shifts. volume was used as a template with a base resolution of 3 
3  4 mm3. This template was duplicated 120 times to gener-
five slice-shifted LR volume datasets. In the slice-shifted ate a dynamic time series, with different ‘activated regions’
mode, the slice thickness was doubled as compared to the stan- inserted in an interleaved mode of 10 ‘rest’ volumes and 10
dard sequence. The two shifted volumes were acquired con- ‘activated’ volumes. These ‘activation’ regions consisted of
secutively, with the second volume shifted in a slice position different spheres with different radii and an irregularly
over a distance equal to the slice thickness of the HR shaped area at carefully chosen positions. The intensity of acti-
images. The high-resolution data were collected on a vation was set to a maximum of 8% peak signal change. Two
Siemens Sonata 1.5 Tesla MR system. A matrix of 128  slice-shifted LR datasets were generated by addition of the
128 was acquired. Voxel size was taken as 2  2  2 mm3 adjacent slices of the HR dataset. Gaussian noise was inserted
for the ground-truth (HR) images and 2  2  4 mm3 for the with a standard deviation of 2% for the HR set and 1% for the
slice-shifted images. The global acquisition time of the high- LR volumes. Figure 13 shows the statistical analysis on
resolution volume was 3328 ms and each of the slice-shifted the synthetic dataset, with similar conclusions obtained as in
interleaved volumes was 1664 ms (for additional acquisition the real dataset. Both 1-D and 3-D SR anisotropic datasets
protocol details see [4]). extract the activated areas in good agreement with the position
Figure 12 shows statistical parametric mapping (SPM) acti- and size of the simulated activated areas.
vation maps [30], displaying the activated areas above a stati- Quantitative measures of the ability to separate two
stical threshold (pcorr , 0.05), overlaid on the mean EPI slices close-by-activated areas were extracted. Figure 14 shows the
of the interpolated datasets. Patches of color on the MRI brain line graphs of calculated t-values of a cut in the slice direction
slice shows differences in brain activity, with the colors repre- through two activated regions, with a separation of two slices
senting the location of voxels that have shown statistically sig- in Fig. 14a and a single slice in Fig. 14b. The results demon-
nificant differences between experimental conditions (see strate that the SR algorithms show a good separation, closely
Appendix A). Figure 12a displays the images of the retino- resembling the HR dataset and much better that in the LR
topic mapping fMRI experiment in the acquisition plane input and average or interleaved datasets.
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
4. SR IN PET
right): original HR and LR inputs, an ‘average’ dataset in
which each HR voxel is computed as the average of all LR In this section, we focus on the application of SR to PET. We
voxels that contain it (equivalent to the initial guess step of discuss the resolution limitations in PET and the challenges for
Irani – Peleg), two SR results, and a ‘composed’ result, SR in PET. Recent works that have started to investigate the
which is equivalent to interleaving. In the SR algorithm, the potential of SR in this domain are reviewed herein.
regularization term was applied in all three dimensions (‘Ani- PET resolution is limited by physical properties, such as
sotropic 3-D’) or in the slice-select only (‘Anisotropic 1-D’). scatter, counting statistics, positron range and patient
Qualitative analysis of the results indicates overall simi- motion, as well as by the detector array geometry and the
larity between the interpolated datasets and the reference implemented acquisition protocol. Detector widths are
HR dataset. A closer look at the data reveals that the 1-D limited to a certain minimal size, due to SNR considerations.
and 3-D anisotropic SR datasets show higher t values at the A width that is too small will reduce detection efficiency and
foci of the activated areas than the reference HR, the original will increase intercrystal scatter and penetration. Resolution in

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 54 H. GREENSPAN

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 accep-
table 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 first 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 typi-
cally rebinned into transverse planes [32] and then recon-
structed 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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 SR IN MEDICAL IMAGING 55

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 gene-
rated 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 final reconstructed resolution
of a PET image is usually poorer than the best obtainable,
intrinsic resolution, because reconstruction algorithms typi-
cally trade-off resolution for reduced noise. In [16], an
example is given where the intrinsic resolution is ,5 mm
yet the final 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 briefly outlined above result in
an under-sampling of available data. Wider detectors define 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 cer-
ebral 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 beneficial 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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 56
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 identified 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 resol-
ution 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 field 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
modification to the PET scanner hardware.
4.1. Experiments and results
In [5], an SR scheme based on the Irani– Peleg iterative algor-
ithm is proposed and experimentally confirmed 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 con-
structed as shown in Fig. 16. The phantom contained holes
of sizes 1, 1.5, 2, 4, 6 and 8 mm in diameter. Several exper-
imental scenarios were tested: 1-D axial shifts (equivalent to
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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 cen-
tered in the FOV of the PET scanner. The scanner was pro-
grammed 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 predefined error was reached, or 16 iterations.
The final 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 deter-
mine the geometric shifts between successive images. In this
example, between the initial PET image (Fig. 17b) and the
FIGURE 16. Phantom disk for PET experimentations ([5], #2006
IEEE).
 SR IN MEDICAL IMAGING 57

TABLE 2. Contrast ratio C for the PET signals in 3-D AC brain

mode acquisition phantom trials ([5] #2006 IEEE)

Image type 3-mm 4-mm 6-mm 8-mm

holes holes holes holes
Coronal
No SR N/Ra N/R 2.1 2.9
Four acquisitions 1.1 1.3 2.4 3.0
interleaved
SR 1.1 1.5 2.8 3.5
Transaxial
No SR N/R 1.2 2.2 2.7
SR 1.2 1.8 3.2 3.8
a
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 definition 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 calcu-
lated to be 4.1 mm FWHM with the SR algorithm, which is
superior to both interleaving (4.9 mm FWHM) and the stan-
dard 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 Axis Standard Interleave SR
mode (mm) (mm) (mm)

2-D whole body Axial 4.8 to 8.6a 4.1

3-D brain Axial 5.3 to 8.7 4.8
3-D brain Radial 5.2 to 5.5 N/Ab 4.3
3-D brain Tangential 4.9 to 5.2 N/A 4.3
FIGURE 18. 3-D brain mode acquisition—results. (a) Standard
a
coronal PET image. (b) Coronal image with SR. (c) Standard transax- Point source either centered in a pixel (lower value) or between
ial PET image. (d) Transaxial with SR ([5], #2006 IEEE). two pixels (upper value).
b
N/A, not applicable.

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 58 H. GREENSPAN

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 18F—FDG PET image using clinical reconstruction protocols. Image planes dis-
played 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 sec-
ondary 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 demon-
strated 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 field 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 demon-
strated 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 smooth-
ness 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 diffu-
sion 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 filter 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 inves-
tigated: first, a more accurate SR algorithm was defined, in
which both the blur kernel as well as the BP kernel are

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 SR IN
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 edge-
enhancement 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 substan-
tial 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 motiv-
ated, 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 con-
tribution 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?
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 fre-
quency content, as output in the reconstructed image. SR
reconstructs the aliased high frequency information thus pro-
viding 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 sub-
millimeter isotropic resolution in less than 30 seconds, with an
effective slice thickness of 0.1 – 0.2 mm. Although the detec-
tors’ sampling looks very promising, it is difficult 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 discus-
sion on the PSF of the CT system, see [37]). Thus, in spiral CT,
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MEDICAL IMAGING 59
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 pitch—the ‘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
Newly emerging hardware may provide additional means for
resolution augmentation. In the MRI field, new parallel
imaging techniques are currently being developed. Such tech-
niques 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 tech-
nologies 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 specific details per modality were presented, including
certain pre-processing and post-processing steps. The reader
is advised to consult the related literature for more specific
implementation details. The overview is definitely not exhaus-
tive: 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 front—finding the applications that may gain most
from the SR technology and implementing the theory in the
clinical practice. On the SR algorithmic front—extending the
investigation into additional medical imaging modalities as
well as comparing between SR algorithms to find the advan-
tages of each per modality. A small number of studies have
recently attempted to compare the performance of SR algor-
ithms 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 three-
way relationship exists between SR, image segmentation and
image registration. It is our conjecture that future research in
the field will focus on strengthening this three-way relation-
ship. Augmented resolution of an image can augment its regis-
tration to another image or to an atlas, and it can, of course,
 60
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 field, 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 con-
strained to a cradle and is less likely to move during the scan.
For the more general case of a moving subject or organ, accu-
rate 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
field 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 regulariz-
ation 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 infor-
mation within the regularization framework. Important infor-
mation 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.
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61
APPENDIX A: A BRIEF INTRODUCTION TO
MEDICAL IMAGING MODALITIES
A.1. Magnetic resonance imaging
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 field, the particle’s 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 field 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 field,
which varies spatially (e.g. changes linearly in all three direc-
tions), 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 defined by ‘slice selection’, in which an RF pulse of
defined bandwidth is applied in the presence of a magnetic
field gradient in order to reduce spatial encoding to two dimen-
sions. 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 first selects the 2-D slice to be ana-
lyzed, 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 predefined 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 deter-
mined by several time constants, each of which reflects a
certain relaxation process that establishes equilibrium follow-
ing 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 field 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
 62
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 field inhomogene-
ities. A subtle but important variant of the T2 technique is
called T2* imaging, which is performed without the refocus-
ing. This sacrifices some image integrity in order to provide
additional sensitivity to relaxation processes that cause inco-
herence 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 fiber tracts (nerve connections)
to appear white, congregations of neurons to appear gray and
cerebrospinal fluid to appear dark. The contrast of ‘white
matter’, ‘gray matter’ and ‘cerebrospinal fluid’ is reversed
using T2 or T2* imaging, whereas proton-weighted imaging
provides less contrast in normal subjects. Various MRI
sequences exist, each defined 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 influ-
ence 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 fluid
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 appli-
cation 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 magni-
tude of the diffusion. The more attenuated the image is at a
given position, the more diffusion there is locally. The
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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 fiber tracts in vivo by identify-
ing 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 mol-
ecules along their main direction. If we apply diffusion gradi-
ents (i.e. magnetic field 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 fiber direction is indicated by the tensor s main eigenvector.
An example image is shown in Figure 3(d) where the bright-
ness is weighted by the tracts anisotropy. HR DTI, combined
with algorithms for tracing fibers in three-dimensions in tensor
fields, has the potential to enable fiber 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 flow to the specific thought
center in the brain. For example, when moving a finger there
is a rapid momentary increase in the circulation of the specific
part of the brain controlling the finger 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 oxy-
genation level-dependent (BOLD) contrast. Higher BOLD
signal intensities arise from decreases in the concentration of
deoxygenated hemoglobin since the blood magnetic suscepti-
bility now more closely matches the tissue magnetic suscepti-
bility. 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
 SR IN
representing the location of voxels that have shown statisti-
cally significant 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)
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 incremen-
tally. 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 coefficient distribution of the cross-
section. 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 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 introduc-
tion 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 patient’s
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
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MEDICAL IMAGING 63
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)
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 specific 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 elec-
tron 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 coordi-
nates 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 (line-
integral 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.