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1.  Dual Inversion Recovery Ultrashort Echo Time (DIR-UTE) Imaging and Quantification of the Zone of Calcified Cartilage (ZCC) 
To develop ultrashort echo time (UTE) magnetic resonance imaging (MRI) techniques to image the zone of calcified cartilage (ZCC), and quantify its T2*, T1 and T1ρ.
In this feasibility study a dual inversion recovery ultrashort echo time (DIR-UTE) sequence was developed for high contrast imaging of the ZCC. T2* of the ZCC was measured with DIR-UTE acquisitions at progressively increasing TEs. T1 of the ZCC was measured with saturation recovery UTE acquisitions at progressively increasing saturation recovery times. T1ρ of the ZCC was measured with spin-locking prepared DIR-UTE acquisitions at progressively increasing spin-locking times.
The feasibility of the qualitative and quantitative DIR-UTE techniques was demonstrated on phantoms and in six cadaveric patellae using a clinical 3T scanner. On average the ZCC has a short T2* ranging from 1.0 to 3.3 ms (mean ± standard deviation = 2.0 ± 1.2 ms), a short T1 ranging from 256 to 389 ms (mean ± standard deviation = 305 ± 45 ms), and a short T1ρ ranging from 2.2 to 4.6 ms (mean ± standard deviation = 3.6 ± 1.2 ms).
UTE MR based techniques have been developed for high resolution imaging of the ZCC and quantitative evaluation of its T2*, T1 and T1ρ relaxation times, providing noninvasive assessment of collagen orientation and proteoglycan content at the zone of calcified cartilage and the bone cartilage interface. These measurements may be useful for non-invasive assessment of the ZCC, including understanding the involvement of this tissue component in osteoarthritis.
PMCID: PMC4051156  PMID: 23025927
Ultrashort echo time; adiabatic inversion recovery; dual inversion recovery; T1ρ; ZCC
2.  State-Dependent Disruption of Short-Term Facilitation Due to Overexpression of the apPDE4 Supershort Form in Aplysia 
Molecules and Cells  2011;31(2):175-180.
Phosphodiesterases (PDEs) play important roles in synaptic plasticity by regulating cAMP signaling in various organisms. The supershort, short, and long forms of Aplysia PDE4 (apPDE4) have been cloned, and the long form has been shown to play a crucial role in 5- hydroxytryptamine (5-HT)-induced synaptic plasticity in Aplysia. To address the role of the supershort form in 5-HT-induced synaptic plasticity in Aplysia, we overexpressed the apPDE4 supershort form in Aplysia sensory neurons. Consequently, 5-HT-induced hyperexcitability and short-term facilitation in nondepressed synapses were blocked. However, the supershort form did not inhibit 5-HT-induced short-term facilitation in highly depressed synapses. These results show that the supershort form plays an important role in 5-HT-induced synaptic plasticity and disrupts it mainly by impairing cAMP signaling in Aplysia.
PMCID: PMC3932685  PMID: 21229325
Aplysia; depressed synapse; PDE4; supershort form; synaptic facilitation
3.  Ultrashort Echo Time (UTE) Magnetic Resonance Imaging of the Short T2 Components in White Matter of the Brain Using a Clinical 3T Scanner 
NeuroImage  2013;87:32-41.
White matter of the brain contains a majority of long T2 components as well as a minority of short T2 components. These are not detectable using clinical magnetic resonance imaging (MRI) sequences with conventional echo times (TEs). In this study we used ultrashort echo time (UTE) sequences to investigate the ultrashort T2 components in white matter of the brain and quantify their T2*s and relative proton densities (RPDs) (relative to water with a proton density of 100%) using a clinical whole body 3T scanner. An adiabatic inversion recovery prepared dual echo UTE (IR-dUTE) sequence was used for morphological imaging of the ultrashort T2 components in white matter. IR-dUTE acquisitions at a constant TR of 1000 ms and a series of TIs were performed to determine the optimal TI which corresponded to the minimum signal to noise ratio (SNR) in white matter of the brain on the second echo image. T2*s of the ultrashort T2 components were quantified using mono-exponential decay fitting of the IR-dUTE signal at a series of TEs. RPD was quantified by comparing IR-dUTE signal of the ultrashort T2 components with that of a rubber phantom. Nine healthy volunteers were studied. The IR-dUTE sequence provided excellent image contrast for the ultrashort T2 components in white matter of the brain with a mean signal to noise ratio of 18.7 ± 3.7 and a contrast to noise ratio of 14.6 ± 2.4 between the ultrashort T2 white matter and gray matter in a 4.4 min scan time with a nominal voxel size of 1.25×1.25×5.0 mm3. On average a T2* value of 0.42 ± 0.08 ms and a RPD of 4.05 ± 0.88% were demonstrated for the ultrashort T2 components in white matter of the brain of healthy volunteers at 3T.
PMCID: PMC4091919  PMID: 24188809
Ultrashort echo time; adiabatic IR; ultrashort T2; white matter; T2*; proton density
4.  Ultrashort T2* Relaxometry for Quantitation of Highly Concentrated Superparamagnetic Iron Oxide (SPIO) Nanoparticle Labeled Cells 
Magnetic Resonance in Medicine  2009;61(4):761-766.
A new method was developed to measure ultrashort T2* relaxation in tissues that contain a focal area of superparamagnetic iron oxide (SPIO) nanoparticle labeled cells in which the T2* decay is too short to be accurately measured using regular multiple gradient echo T2* mapping. The proposed method utilizes the relatively long T2 relaxation of SPIO labeled cells and acquires a series of spin echo images with the readout echo shifted to sample the T2* decay curve. MRI experiments in phantoms and rats with SPIO labeled tumors demonstrated that this method can detect ultrashort T2* down to 1 millisecond or less. Compared to the ultrashort TE technique, the SSE method overestimates the T2* values by about 11%. The longer the TE, the more the measurements deviates from the UTE technique. Combined with the regular multiple gradient echo T2* mapping, the new technique is expected to provide in vivo quantitation of highly concentrated iron labeled cells in tissues from direct cell transplantation.
PMCID: PMC3384488  PMID: 19191285
Superparamagnetic iron oxide nanoparticles; cell labeling; T2* relaxometry
5.  Qualitative and quantitative ultrashort-TE MRI of cortical bone 
NMR in biomedicine  2012;26(5):489-506.
Osteoporosis causes over 1.5 million fractures per year, costing about $15 billion annually in the USA. Current guidelines utilize bone mineral density (BMD) to assess fracture risk; however, BMD alone only accounts for 30–50% of fractures. The other two major components of bone, organic matrix and water, contribute significantly to bone mechanical properties, but cannot be assessed with conventional imaging techniques in spite of the fact that they make up about 57% of cortical bone by volume. Conventional clinical MRI usually detects signals from water in tissues without difficulty, but cannot detect the water bound to the organic matrix, or the free water in the microscopic pores of the Haversian and the lacunar-canalicular system of cortical bone, because of their very short apparent transverse relaxation times (T2*). In recent years, a new class of sequences, ultrashort-TE (UTE) sequences, with nominal TEs of less than 100 μs, which are much shorter than the TEs available with conventional sequences, have received increasing interest. These sequences can detect water signals from within cortical bone and provide an opportunity to study disease of this tissue in a new way. This review summarizes the recent developments in qualitative UTE imaging (techniques and contrast mechanisms to produce bone images with high contrast) and quantitative UTE imaging (techniques to quantify the MR properties, including T1, T2* and the magnetization transfer ratio, and tissue properties, including bone perfusion, as well as total, bound and free water content) of cortical bone in vitro and in vivo. The limitations of the current techniques for clinical applications and future directions are also discussed.
PMCID: PMC4206448  PMID: 23280581
cortical bone; osteoporosis; ultrashort TE; contrast mechanism; T1; T2*; bound water; free water
6.  Ultrashort Echo Time for Improved Positive-Contrast Manganese-Enhanced MRI of Cancer 
PLoS ONE  2013;8(3):e58617.
Manganese (Mn) is a positive magnetic resonance imaging (MRI) contrast agent that has been used to obtain physiological, biochemical, and molecular biological information. There is great interest to broaden its applications, but a major challenge is to increase detection sensitivity. Another challenge is distinguishing regions of Mn-related signal enhancement from background tissue with inherently similar contrast. To overcome these limitations, this study investigates the use of ultrashort echo time (UTE) and subtraction UTE (SubUTE) imaging for more sensitive and specific determination of Mn accumulation.
Materials and Methods
Simulations were performed to investigate the feasibility of UTE and SubUTE for Mn-enhanced MRI and to optimize imaging parameters. Phantoms containing aqueous Mn solutions were imaged on a MRI scanner to validate simulations predictions. Breast cancer cells that are very aggressive (MDA-MB-231 and a more aggressive variant LM2) and a less aggressive cell line (MCF7) were labeled with Mn and imaged on MRI. All imaging was performed on a 3 Tesla scanner and compared UTE and SubUTE against conventional T1-weighted spoiled gradient echo (SPGR) imaging.
Simulations and phantom imaging demonstrated that UTE and SubUTE provided sustained and linearly increasing positive contrast over a wide range of Mn concentrations, whereas conventional SPGR displayed signal plateau and eventual decrease. Higher flip angles are optimal for imaging higher Mn concentrations. Breast cancer cell imaging demonstrated that UTE and SubUTE provided high sensitivity, with SubUTE providing background suppression for improved specificity and eliminating the need for a pre-contrast baseline image. The SubUTE sequence allowed the best distinction of aggressive breast cancer cells.
UTE and SubUTE allow more sensitive and specific positive-contrast detection of Mn enhancement. This imaging capability can potentially open many new doors for Mn-enhanced MRI in vascular, cellular, and molecular imaging.
PMCID: PMC3587583  PMID: 23484042
7.  Effects of fMRI-EEG Mismatches in Cortical Current Density Estimation Integrating fMRI and EEG: A Simulation Study 
Multimodal functional neuroimaging by combining functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) has been studied to achieve high-resolution reconstruction of the spatiotemporal cortical current density (CCD) distribution. However, mismatches between these two imaging modalities may occur due to their different underlying mechanisms. The aim of the present study is to investigate the effects of different types of fMRI-EEG mismatches, including fMRI invisible sources, fMRI extra regions and fMRI displacement, on the fMRI-constrained cortical imaging in a computer simulation based on realistic-geometry boundary-element-method (BEM) model.
Two methods have been adopted to integrate the synthetic fMRI and EEG data for CCD imaging. In addition to the well-known 90% fMRI-constrained Wiener filter approach (Liu AK, Belliveau JW and Dale AM, PNAS, 95: 8945–8950, 1998), we propose a novel two-step algorithm (referred to as “Twomey algorithm”) for fMRI-EEG integration. In the first step, a “hard” spatial prior derived from fMRI is imposed to solve the EEG inverse problem with a reduced source space; in the second step, the fMRI constraint is removed and the source estimate from the first step is re-entered as the initial guess of the desired solution into an EEG least squares fitting procedure with Twomey regularization. Twomey regularization is a modified Tikhonov technique that attempts to simultaneously minimize the distance between the desired solution and the initial estimate, and the residual errors of fitness to EEG data. The performance of the proposed Twomey algorithm has been evaluated both qualitatively and quantitatively along with the lead-field normalized minimum norm (WMN) and the 90% fMRI-weighted Wiener filter approach, under repeated and randomized source configurations. Point spread function (PSF) and localization error (LE) are used to measure the performance of different imaging approaches with or without a variety of fMRI-EEG mismatches.
The results of the simulation show that the Twomey algorithm can successfully reduce the PSF of fMRI invisible sources compared to the Wiener estimation, without losing the merit of having much lower PSF of fMRI visible sources relative to the WMN solution. In addition, the existence of fMRI extra sources does not significantly affect the accuracy of the fMRI-EEG integrated CCD estimation for both the Wiener filter method and the proposed Twomey algorithm, while the Twomey algorithm may further reduce the chance of occurring spurious sources in the extra fMRI regions. The fMRI displacement away from the electrical source causes enlarged localization error in the imaging results of both the Twomey and Wiener approaches, while Twomey gives smaller LE than Wiener with the fMRI displacement ranging from 1-cm to 2-cm. With less than 2-cm fMRI displacement, the LEs for the Twomey and Wiener approaches are still smaller than in the WMN solution.
The present study suggests that the presence of fMRI invisible sources is the most problematic factor responsible for the error of fMRI-EEG integrated imaging based on the Wiener filter approach, whereas this approach is relatively robust against the fMRI extra regions and small displacement between fMRI activation and electrical current sources. While maintaining the above advantages possessed by the Wiener filter approach, the Twomey algorithm can further effectively alleviate the underestimation of fMRI invisible sources, suppress fMRI spurious sources and improve the robustness against fMRI displacement. Therefore, the Twomey algorithm is expected to improve the reliability of multimodal cortical source imaging against fMRI-EEG mismatches.
The proposed method promises to provide a useful alternative for multimodal neuroimaging integrating fMRI and EEG.
PMCID: PMC1945186  PMID: 16765085
multimodal neuroimaging; EEG; fMRI; lead-field normalized minimum norm; point spread function; Twomey regularization; Wiener estimation; boundary element method
8.  Quantitative MRI measurements of the Achilles tendon in spondyloarthritis using ultrashort echo times 
The British Journal of Radiology  2012;85(1015):e293-e299.
Tendon involvement is common in spondyloarthritis. The MRI signal from the Achilles tendon has been used to quantify mechanical tendinopathy; however, conventional MRI is limited by the short T2 of normal tendon. Short and ultrashort echo time (UTE) MRI have the potential to better measure signal intensity reflecting changes in T2 or gadolinium enhancement. Furthermore, UTE images could be used for normalisation to reduce variability. The aim of this work was to investigate such techniques in patients with spondyloarthritis (SpA).
The Achilles tendons of 14 healthy volunteers and 24 patients with symptomatic spondyloarthritis were studied. Combined UTE (TE=0.07 ms) and gradient echo (TE=4.9 ms) images were acquired before and after intravenous gadolinium together with pre-contrast gradient echo images (TE=2 ms). The signal intensity from a region of interest in the Achilles tendon above the calcaneus was measured. The relative enhancement at echo times of 0.07 ms (RE0.1) and 4.9 ms (RE5) were calculated. The ratios of the signal intensities from both 4.9 ms and 2 ms gradient echo images to the signal intensity from the UTE image were calculated (RTE5 and RTE2 respectively).
Interobserver intraclass correlation coefficients were excellent (≥0.97). The contrast-to-noise ratio was higher for enhancement on UTE images than on gradient echo images. RE0.1, RTE5 and RTE2 were significantly higher in SpA patients than controls.
Signal intensity ratios using UTE images allow quantitative measurements to be made which are sensitive to tendon T2 or contrast enhancement and which are increased in spondyloarthritis. They therefore have the potential for use as measures of tendon disease in spondyloarthritis.
PMCID: PMC3474080  PMID: 22745209
9.  Image fusion for dynamic contrast enhanced magnetic resonance imaging 
Multivariate imaging techniques such as dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) have been shown to provide valuable information for medical diagnosis. Even though these techniques provide new information, integrating and evaluating the much wider range of information is a challenging task for the human observer. This task may be assisted with the use of image fusion algorithms.
In this paper, image fusion based on Kernel Principal Component Analysis (KPCA) is proposed for the first time. It is demonstrated that a priori knowledge about the data domain can be easily incorporated into the parametrisation of the KPCA, leading to task-oriented visualisations of the multivariate data. The results of the fusion process are compared with those of the well-known and established standard linear Principal Component Analysis (PCA) by means of temporal sequences of 3D MRI volumes from six patients who took part in a breast cancer screening study.
The PCA and KPCA algorithms are able to integrate information from a sequence of MRI volumes into informative gray value or colour images. By incorporating a priori knowledge, the fusion process can be automated and optimised in order to visualise suspicious lesions with high contrast to normal tissue.
Our machine learning based image fusion approach maps the full signal space of a temporal DCE-MRI sequence to a single meaningful visualisation with good tissue/lesion contrast and thus supports the radiologist during manual image evaluation.
PMCID: PMC529274  PMID: 15494072
10.  Designing Long-T2 Suppression Pulses for Ultrashort Echo Time Imaging 
Ultrashort echo time (UTE) imaging has shown promise as a technique for imaging tissues with T2 values of a few milliseconds or less. These tissues, such as tendons, menisci, and cortical bone, are normally invisible in conventional magnetic resonance imaging techniques but have signal in UTE imaging. They are difficult to visualize because they are often obscured by tissues with longer T2 values. In this article, new long-T2 suppression RF pulses that improve the contrast of short-T2 species are introduced. These pulses are improvements over previous long-T2 suppression pulses that suffered from poor off-resonance characteristics or T1 sensitivity. Short-T2 tissue contrast can also be improved by suppressing fat in some applications. Dual-band long-T2 suppression pulses that additionally suppress fat are also introduced. Simulations, along with phantom and in vivo experiments using 2D and 3D UTE imaging, demonstrate the feasibility, improved contrast, and improved sensitivity of these new long-T2 suppression pulses. The resulting images show predominantly short-T2 species, while most long-T2 species are suppressed.
PMCID: PMC2942755  PMID: 16724304
ultrashort echo time (UTE) imaging; long-T2 suppression; T2 contrast; short-T2 imaging; RF pulse design
Journal of orofacial pain  2011;25(4):345-353.
To quantify short T2* properties of a disc from human temporomandibular joint (TMJ) using ultrashort time-to-echo magnetic resonance imaging (UTE MRI) technique, and to corroborate regional T2* values with biomechanical properties and histologic appearance.
A cadaveric human TMJ was sliced sagittally and imaged using conventional and UTE MRI techniques. The slices were then subjected to either biomechanical indentation testing or histologic evaluation for comparison to T2* maps obtained from UTE MRI data, using linear regression. Feasibility of in vivo UTE MRI was assessed in two volunteers.
UTE MRI technique of specimens provided images of TMJ disc with greater signal-to-noise ratio (~3 fold) and contrast against surrounding tissues compared to conventional techniques. Higher T2* values correlated with lower indentation stiffness (softer) and less collagen organization as indicated by polarized light microscopy. T2* values were also obtained from volunteers.
UTE MRI facilitates quantitative characterization of TMJ discs, which may reflect structural and functional properties related to TMJ dysfunction.
PMCID: PMC4048068  PMID: 22247930
temporomandibular joint disc; magnetic resonance imaging; ultrashort time-to-echo; osteoarthritis; indentation
12.  Simulating Magnetic Nanoparticle Behavior in Low-field MRI under Transverse Rotating Fields and Imposed Fluid Flow 
In the presence of alternating-sinusoidal or rotating magnetic fields, magnetic nanoparticles will act to realign their magnetic moment with the applied magnetic field. The realignment is characterized by the nanoparticle’s time constant, τ. As the magnetic field frequency is increased, the nanoparticle’s magnetic moment lags the applied magnetic field at a constant angle for a given frequency, Ω, in rad/s. Associated with this misalignment is a power dissipation that increases the bulk magnetic fluid’s temperature which has been utilized as a method of magnetic nanoparticle hyperthermia, particularly suited for cancer in low-perfusion tissue (e.g., breast) where temperature increases of between 4°C and 7°C above the ambient in vivo temperature cause tumor hyperthermia. This work examines the rise in the magnetic fluid’s temperature in the MRI environment which is characterized by a large DC field, B0. Theoretical analysis and simulation is used to predict the effect of both alternating-sinusoidal and rotating magnetic fields transverse to B0. Results are presented for the expected temperature increase in small tumors (~1 cm radius) over an appropriate range of magnetic fluid concentrations (0.002 to 0.01 solid volume fraction) and nanoparticle radii (1 to 10 nm). The results indicate that significant heating can take place, even in low-field MRI systems where magnetic fluid saturation is not significant, with careful The goal of this work is to examine, by means of analysis and simulation, the concept of interactive fluid magnetization using the dynamic behavior of superparamagnetic iron oxide nanoparticle suspensions in the MRI environment. In addition to the usual magnetic fields associated with MRI, a rotating magnetic field is applied transverse to the main B0 field of the MRI. Additional or modified magnetic fields have been previously proposed for hyperthermia and targeted drug delivery within MRI. Analytical predictions and numerical simulations of the transverse rotating magnetic field in the presence of B0 are investigated to demonstrate the effect of Ω, the rotating field frequency, and the magnetic field amplitude on the fluid suspension magnetization. The transverse magnetization due to the rotating transverse field shows strong dependence on the characteristic time constant of the fluid suspension, τ. The analysis shows that as the rotating field frequency increases so that Ωτ approaches unity, the transverse fluid magnetization vector is significantly non-aligned with the applied rotating field and the magnetization’s magnitude is a strong function of the field frequency. In this frequency range, the fluid’s transverse magnetization is controlled by the applied field which is determined by the operator. The phenomenon, which is due to the physical rotation of the magnetic nanoparticles in the suspension, is demonstrated analytically when the nanoparticles are present in high concentrations (1 to 3% solid volume fractions) more typical of hyperthermia rather than in clinical imaging applications, and in low MRI field strengths (such as open MRI systems), where the magnetic nanoparticles are not magnetically saturated. The effect of imposed Poiseuille flow in a planar channel geometry and changing nanoparticle concentration is examined. The work represents the first known attempt to analyze the dynamic behavior of magnetic nanoparticles in the MRI environment including the effects of the magnetic nanoparticle spin-velocity. It is shown that the magnitude of the transverse magnetization is a strong function of the rotating transverse field frequency. Interactive fluid magnetization effects are predicted due to non-uniform fluid magnetization in planar Poiseuille flow with high nanoparticle concentrations.
PMCID: PMC2901184  PMID: 20625540
Magnetic nanoparticles; MRI; rotating magnetic field; interactive magnetization; magnetic particle imaging
13.  Dynamic contrast-enhanced magnetic resonance imaging: fundamentals and application to the evaluation of the peripheral perfusion 
The ability to ascertain information pertaining to peripheral perfusion through the analysis of tissues’ temporal reaction to the inflow of contrast agent (CA) was first recognized in the early 1990’s. Similar to other functional magnetic resonance imaging (MRI) techniques such as arterial spin labeling (ASL) and blood oxygen level-dependent (BOLD) MRI, dynamic contrast-enhanced MRI (DCE-MRI) was at first restricted to studies of the brain. Over the last two decades the spectrum of ailments, which have been studied with DCE-MRI, has been extensively broadened and has come to include pathologies of the heart notably infarction, stroke and further cerebral afflictions, a wide range of neoplasms with an emphasis on antiangiogenic treatment and early detection, as well as investigations of the peripheral vascular and musculoskeletal systems.
Applications to peripheral perfusion
DCE-MRI possesses an unparalleled capacity to quantitatively measure not only perfusion but also other diverse microvascular parameters such as vessel permeability and fluid volume fractions. More over the method is capable of not only assessing blood flowing through an organ, but in contrast to other noninvasive methods, the actual tissue perfusion. These unique features have recently found growing application in the study of the peripheral vascular system and most notably in the diagnosis and treatment of peripheral arterial occlusive disease (PAOD).
Review outline
The first part of this review will elucidate the fundamentals of data acquisition and interpretation of DCE-MRI, two areas that often remain baffling to the clinical and investigating physician because of their complexity. The second part will discuss developments and exciting perspectives of DCE-MRI regarding the assessment of perfusion in the extremities. Emerging clinical applications of DCE-MRI will be reviewed with a special focus on investigation of physiology and pathophysiology of the microvascular and vascular systems of the extremities.
PMCID: PMC3996240  PMID: 24834412
Magnetic resonance imaging (MRI); dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI); peripheral artery disease
14.  Optimization of Iron Oxide Nanoparticle Detection Using Ultrashort TE Pulse Sequences: Comparison of T1, T2* and Synergistic T1-T2* Contrast Mechanisms 
Iron oxide nanoparticles (IONPs) are used in various MRI applications as negative contrast agents. A major challenge is to distinguish regions of signal void due to IONPs from those due to low signal tissues or susceptibility artifacts. To overcome this limitation, several positive contrast strategies have been proposed. Relying on IONP T1 shortening effects to generate positive contrast is a particularly appealing strategy since it should provide additional specificity when associated with the usual negative contrast from T2* effects. In this paper, Ultrashort TE (UTE) imaging is shown to be a powerful technique which can take full advantage of both contrast mechanisms. Methods of comparing T1 and T2* contrast efficiency are described and general rules that allow optimizing IONP detection sensitivity are derived. Contrary to conventional wisdom, optimizing T1 contrast is often a good strategy for imaging IONPs. Under certain conditions, subtraction of a later echo signal from the UTE signal not only improves IONP specificity by providing long T2* background suppression, but also increases detection sensitivity, as it enables a synergistic combination of usually antagonist T1 and T2* contrasts. In vitro experiments support our theory and a molecular imaging application is demonstrated using tumor-targeted IONPs in vivo.
PMCID: PMC3097261  PMID: 21305596
UTE; iron oxide nanoparticle; sequence optimization; positive contrast
15.  Detecting Fleeting MRI Signals with Frequency-Modulated Pulses 
AIP conference proceedings  2011;1330:23-26.
We describe a fundamentally different approach to MRI referred to as SWIFT (sweep imaging with Fourier transformation). SWIFT exploits time-shared RF excitation and signal acquisition, allowing capture of signal from spins with extremely short transverse relaxation time, T2*. The MR signal is acquired in gaps inserted into a broadband frequency-swept excitation pulse, which results in acquisition delays of only 1 – 2 microseconds. In SWIFT, 3D k-space is sampled in a radial manner, whereby one projection of the object is acquired in the gaps of each frequency-swept pulse, allowing a repetition time (TR) on the order of the pulse length (typically 1 – 3 milliseconds). Since the orientation of consecutive projections varies in a smooth manner (i.e., only small increments in the values of the x, y, z gradients occur from view to view), SWIFT scanning is close to inaudible and is insensitive to gradient timing errors and eddy currents. SWIFT images can be acquired in scan times similar to and sometimes faster than conventional 3D gradient echo techniques. With its ability to capture signals from ultrashort T2* spins, SWIFT promises to expand the role of MRI in areas of research where MRI previously played no or negligible role. In this article, we show wood and tooth images obtained with SWIFT as examples of materials with ultrashort T2*. Early experience suggests SWIFT can play a role in materials science and porous media research.
PMCID: PMC3363361  PMID: 22661791
MRI; frequency modulated pulse; correlation spectroscopy; radial imaging; ultrashort T2*
16.  Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (IV): Basic principles and parameters for MR imaging within the frame of image based adaptive cervix cancer brachytherapy 
Radiotherapy and Oncology  2012;103(1):113-122.
The GYN GEC-ESTRO working group issued three parts of recommendations and highlighted the pivotal role of MRI for the successful implementation of 3D image-based cervical cancer brachytherapy (BT). The main advantage of MRI as an imaging modality is its superior soft tissue depiction quality. To exploit the full potential of MRI for the better ability of the radiation oncologist to make the appropriate choice for the BT application technique and to accurately define the target volumes and the organs at risk, certain MR imaging criteria have to be fulfilled. Technical requirements, patient preparation, as well as image acquisition protocols have to be tailored to the needs of 3D image-based BT. The present recommendation is focused on the general principles of MR imaging for 3D image-based BT.
Methods and parameters have been developed and progressively validated from clinical experience from different institutions (IGR, Universities of Vienna, Leuven, Aarhus and Ljubljana) and successfully applied during expert meetings, contouring workshops, as well as within clinical and interobserver studies.
It is useful to perform pelvic MRI scanning prior to radiotherapy (“Pre-RT-MRI examination”) and at the time of BT (“BT MRI examination”) with one MR imager. Both low and high-field imagers, as well as both open and close magnet configurations conform to the requirements of 3D image-based cervical cancer BT. Multiplanar (transversal, sagittal, coronal and oblique image orientation) T2-weighted images obtained with pelvic surface coils are considered as the golden standard for visualisation of the tumour and the critical organs. The use of complementary MRI sequences (e.g. contrast-enhanced T1-weighted or 3D isotropic MRI sequences) is optional. Patient preparation has to be adapted to the needs of BT intervention and MR imaging. It is recommended to visualise and interpret the MR images on dedicated DICOM-viewer workstations, which should also assist the contouring procedure. Choice of imaging parameters and BT equipment is made after taking into account aspects of interaction between imaging and applicator reconstruction, as well as those between imaging, geometry and dose calculation.
In a prospective clinical context, to implement 3D image-based cervical cancer brachytherapy and to take advantage of its full potential, it is essential to successfully meet the MR imaging criteria described in the present recommendations of the GYN GEC-ESTRO working group.
PMCID: PMC3336085  PMID: 22296748
Recommendations; MRI; Image based adaptive cervix cancer brachytherapy
17.  k-Space Water-Fat Decomposition With T2∗ Estimation and Multifrequency Fat Spectrum Modeling for Ultrashort Echo Time Imaging 
To demonstrate the feasibility of combining a chemical shift-based water-fat separation method (IDEAL) with a 2D ultrashort echo time (UTE) sequence for imaging and quantification of the short T2 tissues with robust fat suppression.
Materials and Methods
A 2D multislice UTE data acquisition scheme was combined with IDEAL processing, including T2∗ estimation, chemical shift artifacts correction, and multifrequency modeling of the fat spectrum to image short T2 tissues such as the Achilles tendon and meniscus both in vitro and in vivo. The integration of an advanced field map estimation technique into this combined method, such as region growing (RG), is also investigated.
The combination of IDEAL with UTE imaging is feasible and excellent water-fat separation can be achieved for the Achilles tendon and meniscus with simultaneous T2∗ estimation and chemical shift artifact correction. Multifrequency modeling of the fat spectrum yields more complete water-fat separation with more accurate correction for chemical shift artifacts. The RG scheme helps to avoid water-fat swapping.
The combination of UTE data acquisition with IDEAL has potential applications in imaging and quantifying short T2 tissues, eliminating the necessity for fat suppression pulses that may directly suppress the short T2 signals.
PMCID: PMC3130602  PMID: 20373450
ultrashort TE (UTE); ultrashort TE spectroscopic imaging (UTESI); IDEAL; water-fat separation; T*2 estimation; artifact correction
18.  Sodium Mapping in Focal Cerebral Ischemia in the Rat by Quantitative 23Na MRI 
To validate 23Na twisted projection magnetic resonance imaging (MRI) as a quantitative technique to assess local brain sodium concentration ([Na+]br) during rat focal ischemia every 5.3 minutes.
Materials and Methods
The MRI protocol included an ultrashort echo-time (0.4 msec), a correction of radiofrequency (RF) inhomogeneities by B1 mapping, and the use of 0–154 mM NaCl calibration standards. To compare MRI [Na+]br values with those obtained by emission flame photometry in precision-punched brain samples of about 0.5 mm3 size, MR images were aligned with a histological three-dimensional reconstruction of the punched brain and regions of interest (ROIs) were placed precisely over the punch voids.
The Bland–Altman analysis of [Na+]br in normal and ischemic cortex and caudate putamen of seven rats quantitated by 23Na MRI and flame photometry yielded a mean bias and limits of agreement (at ±1.96 SD) of 2% and 43% of average, respectively. A linear increase in [Na+]br was observed between 1 and 6 hours after middle cerebral artery occlusion.
23Na MRI provides accurate and reliable results within the whole range of [Na+]br in ischemia with a temporal resolution of 5.3 minutes and precisely targeted submicroliter ROIs in selected brain structures.
PMCID: PMC2720271  PMID: 19306443
rat brain; focal ischemia; tissue sodium; 23Na MRI
19.  Quantification in tissue near-infrared spectroscopy 
In near-infrared spectroscopy (NIRS) of tissue, light attenuation is due to: (i) absorption from chromophores of fixed concentration, (ii) absorption from chromophores of variable concentration, and (iii) light scatter. NIRS is usually concerned with trying to quantify the concentrations of chromophores in category (ii), in particular oxy- and deoxyhaemoglobin (HbO2 and Hb) and cytochrome oxidase.
In the absence of scatter the total light absorption in the medium is a linear sum of that due to each chromophore. In a scattering medium like tissue, this linear summation is distorted because the optical path length at each wavelength may differ. This distorted spectrum is then superimposed upon a further wavelength-dependent attenuation arising from light loss due to scatter, which is a complex function of the tissue absorption and scattering coefficients ( μa and μs), scattering phase function, and tissue and measurement geometry. Consequently, quantification of NIRS data is difficult.
Over the past 20 years many differing approaches to quantification have been tried. The development of methods for measuring optical path length in tissue initially enabled changes in concentration to be quantified, and subsequently methods for absolute quantification of HbO2 and Hb were developed by correlating NIRS changes with an independent measurement of arterial haemoglobin saturation. Absolute determination of tissue optical properties, however, requires additional information over and above the detected intensity at the tissue surface, which must then be combined with a model of light transport to derive μa and μs. The additional data can take many forms, e.g. the change in intensity with distance, the temporal dispersion of light from an ultrashort input light pulse, or phase, and modulation depth changes of intensity-modulated light. All these approaches are now being actively pursued with considerable success. However, all the approaches are limited by the accuracy of the light transport models, especially in inhomogeneous media.
PMCID: PMC1691964
Continuous Intensity Spectrometer Intensity Modulated Spectrometer Time Resolved Spectrometer Absolute Quantification Light Distribution
20.  Multicentre imaging measurements for oncology and in the brain 
The British Journal of Radiology  2011;84(Spec Iss 2):S213-S226.
Multicentre imaging studies of brain tumours (and other tumour and brain studies) can enable a large group of patients to be studied, yet they present challenging technical problems. Differences between centres can be characterised, understood and minimised by use of phantoms (test objects) and normal control subjects. Normal white matter forms an excellent standard for some MRI parameters (e.g. diffusion or magnetisation transfer) because the normal biological range is low (<2–3%) and the measurements will reflect this, provided the acquisition sequence is controlled. MR phantoms have benefits and they are necessary for some parameters (e.g. tumour volume). Techniques for temperature monitoring and control are given. In a multicentre study or treatment trial, between-centre variation should be minimised. In a cross-sectional study, all groups should be represented at each centre and the effect of centre added as a covariate in the statistical analysis. In a serial study of disease progression or treatment effect, individual patients should receive all of their scans at the same centre; the power is then limited by the within-subject reproducibility. Sources of variation that are generic to any imaging method and analysis parameters include MR sequence mismatch, B1 errors, CT effective tube potential, region of interest generation and segmentation procedure. Specific tissue parameters are analysed in detail to identify the major sources of variation and the most appropriate phantoms or normal studies. These include dynamic contrast-enhanced and dynamic susceptibility contrast gadolinium imaging, T1, diffusion, magnetisation transfer, spectroscopy, tumour volume, arterial spin labelling and CT perfusion.
PMCID: PMC3473901  PMID: 22433831
21.  Differentiation of Breast Cancer from Fibroadenoma with Dual-Echo Dynamic Contrast-Enhanced MRI 
PLoS ONE  2013;8(7):e67731.
Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) of the breast is a routinely used imaging method which is highly sensitive for detecting breast malignancy. Specificity, though, remains suboptimal. Dynamic susceptibility contrast magnetic resonance imaging (DSC MRI), an alternative dynamic contrast imaging technique, evaluates perfusion-related parameters unique from DCE MRI. Previous work has shown that the combination of DSC MRI with DCE MRI can improve diagnostic specificity, though an additional administration of intravenous contrast is required. Dual-echo MRI can measure both T1W DCE MRI and T2*W DSC MRI parameters with a single contrast bolus, but has not been previously implemented in breast imaging. We have developed a dual-echo gradient-echo sequence to perform such simultaneous measurements in the breast, and use it to calculate the semi-quantitative T1W and T2*W related parameters such as peak enhancement ratio, time of maximal enhancement, regional blood flow, and regional blood volume in 20 malignant lesions and 10 benign fibroadenomas in 38 patients. Imaging parameters were compared to surgical or biopsy obtained tissue samples. Receiver operating characteristic (ROC) curves and area under the ROC curves were calculated for each parameter and combination of parameters. The time of maximal enhancement derived from DCE MRI had a 90% sensitivity and 69% specificity for predicting malignancy. When combined with DSC MRI derived regional blood flow and volume parameters, sensitivity remained unchanged at 90% but specificity increased to 80%. In conclusion, we show that dual-echo MRI with a single administration of contrast agent can simultaneously measure both T1W and T2*W related perfusion and kinetic parameters in the breast and the combination of DCE MRI and DSC MRI parameters improves the diagnostic performance of breast MRI to differentiate breast cancer from benign fibroadenomas.
PMCID: PMC3699626  PMID: 23844077
22.  Optimized 3D Ultrashort Echo Time Pulmonary MRI 
To optimize 3D radial ultrashort echo time MRI for high resolution whole-lung imaging.
3D radial ultrashort echo time was implemented on a 3T scanner to investigate the effects of: (1) limited field-of-view excitation, (2) variable density readouts, and (3) radial oversampling. Improvements in noise performance and spatial resolution were assessed through simulation and phantom studies. Their effects on lung and airway visualization in five healthy male human subjects (mean age 32 years) were compared qualitatively through blinded ordinal scoring by two cardiothoracic radiologists using a nonparametric Friedman test (P < 0.05). Relative signal difference between endobronchial air and adjacent lung tissue, normalized to nearby vessel, was used as a surrogate for lung tissue signal. Quantitative measures were compared using the paired Student's t-test (P < 0.05). Finally, clinical feasibility was investigated in a patient with interstitial fibrosis.
Simulation and phantom studies showed up to 67% improvement in SNR and reduced blurring for short T2* species using all three optimizations. In vivo images showed decreased artifacts and improved lung tissue and airway visualization both qualitatively and quantitatively.
The use of limited field-of-view excitation, variable readout gradients, and radial oversampling significantly improve the technical quality of 3D radial ultrashort echo time lung images.
PMCID: PMC4199575  PMID: 23213020
MRI; lung; ultrashort echo time; radial imaging
23.  UTE-T2* mapping of human articular cartilage in vivo: a repeatability assessment 
Ultrashort echo-time enhanced T2* (UTE-T2*) mapping of articular cartilage is a novel quantitative MRI technique with the potential to visualize deep cartilage characteristics better than standard T2 mapping. The feasibility and intersession repeatability of UTE-T2* mapping of cartilage in vivo has not previously been evaluated.
Eleven asymptomatic subjects underwent repeat UTE-T2* imaging on a whole-body 3T MRI scanner on three consecutive days. Full-thickness, superficial and deep regions of interest (ROIs) were evaluated in the central weight-bearing medial femoral condyle (cMFC) and tibial plateau (cMTP). Intersession precision error across subjects was evaluated by the root-mean-square average coefficients of variation (RMSA-CV) and by the median of intra-subject standard deviations (SD) of UTE-T2* values in each ROIs.
UTE-T2* values in vivo were found to be repeatable with relative (RMSA-CV) intersession precision errors of 8%, 6%, 16% for full-thickness, superficial and deep cMFC ROIs, corresponding to absolute errors (SD) of 1.2, 1.5, 1.5ms, respectively. In cMTP tissue, UTE-T2* relative repeatability was 8%, 8%, 13%, corresponding to absolute repeatability of 1.0, 1.5, 2.1ms (full-thickness, superficial, deep). UTE-T2* values were higher in superficial cartilage compared to deep in both cMFC (p<<0.001) and cMTP (p=0.0004) regions.
In vivo 3-D UTE-T2* mapping at 3T is feasible and can be implemented using a standard clinical MRI scanner and knee coil. Intersession precision error of UTE-T2* values in full-thickness ROIs in the weight-bearing regions of asymptomatic subjects is under 1.2ms or 8% (RMSA-CV). Significant zonal and regional variations of UTE-T2* were seen.
PMCID: PMC3098496  PMID: 21035556
Ultrashort echo time; T2* Mapping; Cartilage
24.  Magnetic resonance imaging assessed cortical porosity is highly correlated with μCT porosity 
Bone  2014;66:56-61.
Cortical bone is typically regarded as “MR invisible” with conventional clinical magnetic resonance imaging (MRI) pulse sequences. However, recent studies have demonstrated that free water in the microscopic pores of cortical bone has a short T2* but a relatively long T2, and may be detectable with conventional clinical spin echo (SE) or fast spin echo (FSE) sequences. In this study we describe the use of a conventional two-dimensional (2D) FSE sequence to assess cortical bone microstructure and measure cortical porosity using a clinical 3T scanner. Twelve cadaveric human cortical bone samples were studied with MRI and micro computed tomography (μCT) (downsampled to the same spatial resolution). Preliminary results show that FSE-determined porosity is highly correlated (R2 = 0.83; P < 0.0001) with μCT porosity. Bland Altman analysis suggested a good agreement between FSE and μCT with tight limit of agreement at around 3%. There is also a small bias of -2% for the FSE data, which suggested that the FSE approach slightly underestimated μCT porosity. The results demonstrate that cortical porosity can be directly assessed using conventional clinical FSE sequences. The clinical feasibility of this approach was also demonstrated on six healthy volunteers using 2D FSE sequences as well as 2D ultrashort echo time (UTE) sequences with a minimal echo time (TE) of 8 μs, which provide high contrast imaging of cortical bone in vivo.
PMCID: PMC4125420  PMID: 24928498
Fast spin echo; UTE; porosity; cortical bone; μCT
25.  Canine and Human Visual Cortex Intact and Responsive Despite Early Retinal Blindness from RPE65 Mutation 
PLoS Medicine  2007;4(6):e230.
RPE65 is an essential molecule in the retinoid-visual cycle, and RPE65 gene mutations cause the congenital human blindness known as Leber congenital amaurosis (LCA). Somatic gene therapy delivered to the retina of blind dogs with an RPE65 mutation dramatically restores retinal physiology and has sparked international interest in human treatment trials for this incurable disease. An unanswered question is how the visual cortex responds after prolonged sensory deprivation from retinal dysfunction. We therefore studied the cortex of RPE65-mutant dogs before and after retinal gene therapy. Then, we inquired whether there is visual pathway integrity and responsivity in adult humans with LCA due to RPE65 mutations (RPE65-LCA).
Methods and Findings
RPE65-mutant dogs were studied with fMRI. Prior to therapy, retinal and subcortical responses to light were markedly diminished, and there were minimal cortical responses within the primary visual areas of the lateral gyrus (activation amplitude mean ± standard deviation [SD] = 0.07% ± 0.06% and volume = 1.3 ± 0.6 cm3). Following therapy, retinal and subcortical response restoration was accompanied by increased amplitude (0.18% ± 0.06%) and volume (8.2 ± 0.8 cm3) of activation within the lateral gyrus (p < 0.005 for both). Cortical recovery occurred rapidly (within a month of treatment) and was persistent (as long as 2.5 y after treatment). Recovery was present even when treatment was provided as late as 1–4 y of age. Human RPE65-LCA patients (ages 18–23 y) were studied with structural magnetic resonance imaging. Optic nerve diameter (3.2 ± 0.5 mm) was within the normal range (3.2 ± 0.3 mm), and occipital cortical white matter density as judged by voxel-based morphometry was slightly but significantly altered (1.3 SD below control average, p = 0.005). Functional magnetic resonance imaging in human RPE65-LCA patients revealed cortical responses with a markedly diminished activation volume (8.8 ± 1.2 cm3) compared to controls (29.7 ± 8.3 cm3, p < 0.001) when stimulated with lower intensity light. Unexpectedly, cortical response volume (41.2 ± 11.1 cm3) was comparable to normal (48.8 ± 3.1 cm3, p = 0.2) with higher intensity light stimulation.
Visual cortical responses dramatically improve after retinal gene therapy in the canine model of RPE65-LCA. Human RPE65-LCA patients have preserved visual pathway anatomy and detectable cortical activation despite limited visual experience. Taken together, the results support the potential for human visual benefit from retinal therapies currently being aimed at restoring vision to the congenitally blind with genetic retinal disease.
The study by Samuel Jacobson and colleagues suggests that retinal gene therapy can improve retinal, visual pathway, and visual cortex responses to light stimulation, even after prolonged periods of blindness and in congenitally blind patients.
Editors' Summary
The eye captures light but the brain is where vision is experienced. Treatments for childhood blindness at the eye level are ready, but it is unknown whether the brain will be receptive to an improved neural message. Normal vision begins as photoreceptor cells in the retina (the light-sensitive tissue lining the inside of the eye) convert visual images into electrical impulses. These impulses are sent along the optic nerve to the visual cortex, the brain region where they are interpreted. The conversion of light into electrical impulses requires the activation of a molecule called retinal, which is subsequently recycled by retinal pigment epithelium (RPE) cells neighboring the retina. One of the key enzymes of the recycling reactions is encoded by a gene called RPE65. Genetic changes (mutations) in RPE65 cause an inherited form of blindness called Leber congenital amaurosis (LCA). In this disease, retinal is not recycled and as a result, the photoreceptor cells cannot work properly and affected individuals have poor or nonexistent vision from birth. Previous studies in dog and mouse models of the human disease have demonstrated that the introduction of a functional copy of RPE65 into the RPE cells using a harmless virus (gene therapy) dramatically restores retinal activity. Very recently, a pioneering gene therapy operation took place in London (UK) where surgeons injected a functional copy of RPE65 into the retina of a man with LCA. Whether this operation results in improved vision is not known at this time.
Why Was This Study Done?
Gene therapy corrects the retinal defects in animal models of LCA but whether the visual pathway from the retina to the visual cortex of the brain can respond normally to the signals sent by the restored retina is not known. Early visual experience is thought to be necessary for the development of a functional visual cortex, so replacing the defective RPE65 gene might not improve the vision of people with LCA. In this study, the researchers have studied the visual cortex of RPE65-deficient dogs before and after gene therapy to see whether the therapy affects the activity of the visual cortex. They have also investigated visual pathway integrity and responsiveness in adults with LCA caused by RPE65 mutations. If the visual pathway is disrupted in these patients, they reasoned, gene therapy might not restore their vision.
What Did the Researchers Do and Find?
The researchers used a technique called functional magnetic resonance imaging (fMRI) to measure light-induced brain activity in RPE65-deficient dogs before and after gene therapy. They also examined the reactions of the dogs' pupils to light (in LCA, the pupils do not contract normally in response to light because there is reduced signal transmission along the visual pathway). Finally, they measured the electrical activity of the dogs' retinas in response to light flashes—the retinas of patients with LCA do not react to light. Gene therapy corrected the defective retinal and visual pathway responses to light in the RPE65-deficient dogs and, whereas before treatment there was no response in the visual cortex to light stimulation in these dogs, after treatment, its activity approached that seen in normal dogs. The recovery of cortical responses was permanent and occurred soon after treatment, even in animals that were 4 years old when treated. Next, using structural MRI, the researchers studied human patients with LCA and found that the optic nerve diameter in young adults was within the normal range and that the structure of the visual cortex was very similar to that of normal individuals. Finally, using fMRI, they found that, although the visual cortex of patients with LCA did not respond to dim light, its reaction to bright light was comparable to that of normal individuals.
What Do These Findings Mean?
The findings from the dog study indicate that retinal gene therapy rapidly improves retinal, visual pathway, and visual cortex responses to light stimulation, even in animals that have been blind for years. In other words, in the dog model of LCA at least, all the components of the visual system remain receptive to visual inputs even after long periods of visual deprivation. The findings from the human study also indicate that the visual pathway remains anatomically intact despite years of disuse and that the visual cortex can be activated in patients with LCA even though these people have very limited visual experience. Taken together, these findings suggest that successful gene therapy of the retina might restore some functional vision to people with LCA but proof will have to await the outcomes of several clinical trials ongoing or being planned in Europe and the USA.
Additional Information.
Please access these Web sites via the online version of this summary at
General information on gene therapy is available from the Oak Ridge National Laboratory
Information is provided by the BBC about gene therapy for Leber congenital amaurosis (includes an audio clip from a doctor about the operation)
The National Institutes of Health/National Eye Institute (US) provides information about an ongoing gene therapy trial of RPE65-Leber congenital amaurosis gives details on treatment trials for Leber congenital amaurosis
The Foundation Fighting Blindness has a fact sheet on Leber congenital amaurosis (site includes Microsoft Webspeak links that read some content aloud)
The Foundation for Retinal Research has a fact sheet on Leber congenital amaurosis
Find more detailed information on Leber congenital amaurosis and the gene mutations that cause it from GeneReviews
WonderBaby, information for parents of babies with Leber congenital amaurosis
PMCID: PMC1896221  PMID: 17594175

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