Differentiation of myeloma and metastatic cancer in the spine using dynamic contrast-enhanced MRI.

Spinal myeloma and metastatic cancer cause similar symptoms and show similar imaging presentations, thus making them difficult to differentiate. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed to differentiate between 9 myelomas and 22 metastatic cancers that present as focal lesions in the spine. The characteristic DCE parameters, including the peak signal enhancement percentage (SE%), the steepest wash-in SE% during the ascending phase and the wash-out SE%, were calculated by normalizing to the precontrast signal intensity. The two-compartmental pharmacokinetic model was used to obtain K(trans) and kep. All nine myelomas showed the wash-out DCE pattern. Of the 22 metastatic cancers, 12 showed wash-out, 7 showed plateau, and 3 showed persistent enhancing patterns. The fraction of cases that showed the wash-out pattern was significantly higher in the myeloma group than the metastatic cancer group (9/9=100% vs. 12/22=55%, P=.03). Compared to the metastatic cancer group, the myeloma group had a higher peak SE% (226%±72% vs. 165%±60%, P=.044), a higher steepest wash-in SE% (169%±51% vs. 111%±41%, P=.01), a higher K(trans) (0.114±0.036 vs. 0.077±0.0281/min, P=.016) and a higher kep (0.88±0.26 vs. 0.49±0.23 1/min, P=.002). The receiver operating characteristic analysis to differentiate between these two groups showed that the area under the curve was 0.798 for K(trans), 0.864 for kep and 0.919 for combined K(trans) and kep. These results show that DCE-MRI may provide additional information for making differential diagnosis to aid in choosing the optimal subsequent procedures or treatments for spinal lesions.

Aquaporin-4-dependent edema clearance following status epilepticus.

We investigated the role of aquaporin-4 in the development of cerebral edema following kainic acid-induced status epilepticus (SE) using specific gravimetry and T2 MRI techniques at 6 h, 1 day, 4 days and 7 days after SE. Our results indicate significantly greater tissue edema and T2 MRI changes in AQP4(-/-) compared to AQP4(+/+) mice that peaks at about 1 day after SE (greater in hippocampus relative to cortex). These results have implications for the mechanisms of edema formation and clearance following intense seizure activity.

Feasibility study of a unilateral RF array coil for MR-scintimammography.

Despite its high sensitivity, the variable specificity of magnetic resonance imaging (MRI) in breast cancer diagnosis can lead to unnecessary biopsies and over-treatment. Scintimammography (SMM) could potentially supplement MRI to improve the diagnostic specificity. The synergistic combination of MRI and SMM (MRSMM) could result in both high sensitivity from MRI and high specificity from SMM. Development of such a dual-modality system requires the integration of a radio frequency (RF) coil and radiation detector in a strong magnetic field without significant mutual interference. In this study, we developed and tested a unilateral breast array coil specialized for MRSMM imaging. The electromagnetic field, specific absorption ratio and RF coil parameters with cadmium-zinc-telluride detectors encapsulated in specialized RF and gamma-ray shielding mounted within the RF coil were investigated through simulation and experimental measurements. Simultaneous MR and SMM images of a breast phantom were also acquired using the integrated MRSMM system. This work, we feel, represents an important step toward the fabrication of a working MRSMM system.

EFEMP1 suppresses malignant glioma growth and exerts its action within the tumor extracellular compartment.

PURPOSE: There are conflicting reports regarding the function of EFEMP1 in different cancer types. In this study, we sought to evaluate the role of EFEMP1 in malignant glioma biology. EXPERIMENTAL DESIGN: Real-time qRT-PCR was used to quantify EFEMP1 expression in 95 glioblastoma multiforme (GBM). Human high-grade glioma cell lines and primary cultures were engineered to express ectopic EFEMP1, a small hairpin RNA of EFEMP1, or treated with exogenous recombinant EFEMP1 protein. Following treatment, growth was assayed both in vitro and in vivo (subcutaneous (s.c.) and intracranial (i.c.) xenograft model systems). RESULTS: Cox regression revealed that EFEMP1 is a favorable prognostic marker for patients with GBM. Over-expression of EFEMP1 eliminated tumor development and suppressed angiogenesis, cell proliferation, and VEGFA expression, while the converse was true with knock-down of endogenous EFEMP1 expression. The EFEMP1 suppression of tumor onset time was nearly restored by ectopic VEGFA expression; however, overall tumor growth rate remained suppressed. This suggested that inhibition of angiogenesis was only partly responsible for EFEMP1's impact on glioma development. In glioma cells that were treated by exogenous EFEMP1 protein or over-expressed endogenous EFEMP1, the EGFR level was reduced and AKT signaling activity attenuated. Mixing of EFEMP1 protein with cells prior to s.c. and i.c. implantations or injection of the protein around the established s.c. xenografts, both significantly suppressed tumorigenicity. CONCLUSIONS: Overall, our data reveals that EEFEMP1 suppresses glioma growth in vivo, both by modulating the tumor extracellular microenvironment and by altering critical intracellular oncogenic signaling pathways.

Simultaneous in vivo dynamic contrast-enhanced magnetic resonance and scintigraphic imaging.

In this study, we investigated the in vivo application of an integrated small-animal magnetic resonance (MR) and gamma-ray imaging system that consists of a semiconductor-based radiation detector, a parallel-hole collimator, and a specialized radiofrequency coil. Gadodiamide and (99m)Tc sestimibi agents were injected simultaneously into a mouse, and simultaneous dynamic contrast-enhanced MR and scintigraphic images of the kidneys were acquired. The time curves of both the MR signal intensity and radioactivity indicate a rapid uptake of the agents followed by a more gradual excretion, consistent with the previously reported literature. Our results demonstrate the feasibility of measuring multiple biological processes at the same time using both MR contrast agents and radiotracers.

Epileptogenesis provoked by prolonged experimental febrile seizures: mechanisms and biomarkers.

Whether long febrile seizures (FSs) can cause epilepsy in the absence of genetic or acquired predisposing factors is unclear. Having established causality between long FSs and limbic epilepsy in an animal model, we studied here if the duration of the inciting FSs influenced the probability of developing subsequent epilepsy and the severity of the spontaneous seizures. We evaluated if interictal epileptifom activity and/or elevation of hippocampal T2 signal on magnetic resonance image (MRI) provided predictive biomarkers for epileptogenesis, and if the inflammatory mediator interleukin-1beta (IL-1beta), an intrinsic element of FS generation, contributed also to subsequent epileptogenesis. We found that febrile status epilepticus, lasting an average of 64 min, increased the severity and duration of subsequent spontaneous seizures compared with FSs averaging 24 min. Interictal activity in rats sustaining febrile status epilepticus was also significantly longer and more robust, and correlated with the presence of hippocampal T2 changes in individual rats. Neither T2 changes nor interictal activity predicted epileptogenesis. Hippocampal levels of IL-1beta were significantly higher for >24 h after prolonged FSs. Chronically, IL-1beta levels were elevated only in rats developing spontaneous limbic seizures after febrile status epilepticus, consistent with a role for this inflammatory mediator in epileptogenesis. Establishing seizure duration as an important determinant in epileptogenesis and defining the predictive roles of interictal activity, MRI, and inflammatory processes are of paramount importance to the clinical understanding of the outcome of FSs, the most common neurological insult in infants and children.

Fourier transform magnetic resonance current density imaging (FT-MRCDI) from one component of magnetic flux density.

Fourier transform (FT)-based algorithms for magnetic resonance current density imaging (MRCDI) from one component of magnetic flux density have been developed for 2D and 3D problems. For 2D problems, where current is confined to the xy-plane and z-component of the magnetic flux density is measured also on the xy-plane inside the object, an iterative FT-MRCDI algorithm is developed by which both the current distribution inside the object and the z-component of the magnetic flux density on the xy-plane outside the object are reconstructed. The method is applied to simulated as well as actual data from phantoms. The effect of measurement error on the spatial resolution of the current density reconstruction is also investigated. For 3D objects an iterative FT-based algorithm is developed whereby the projected current is reconstructed on any slice using as data the Laplacian of the z-component of magnetic flux density measured for that slice. In an injected current MRCDI scenario, the current is not divergence free on the boundary of the object. The method developed in this study also handles this situation.

A PIN diode controlled dual-tuned MRI RF coil and phased array for multi nuclear imaging.

MR imaging of nuclei other than hydrogen has been used to investigate metabolism in humans and animals. However, MRI observable nuclei other than hydrogen are not as abundant and as a result the image SNR is lower. Dual-tuned radio frequency (RF) coils are developed for these studies in which high-resolution structural images are acquired using hydrogen and metabolic information is acquired by exciting the other nucleus. Using a dual-tuned coil, the experimenter avoids the inconvenience of moving the patient out and replacing the RF coil for imaging different nuclei. This also eliminates image registration problems. However, the common scheme of using trap circuits for dual-tuned operation results in increased coil losses as well as problems in obtaining optimal tuning and matching at both frequencies. Here, a new approach is presented using PIN diodes to switch the coil between two resonance frequencies. This design eliminates the need for the trap circuit and associated losses from the self-resistance of the trap circuit inductors. At the operating frequencies we used, the equivalent series resistance of an inductor is higher than that of the PIN diodes. In order to test the efficacy of this new approach, we first built two surface coils of identical geometry, one with the conventional trap circuits and one with the PIN diode switches. We also studied the performances of both coils when the coils are divided into shorter conductors segments by adding more tuning elements. It is known that dividing the coil into shorter conductor segments helps reduce radiation and electric field losses. We explored this effect for both coils at both operating frequencies. Finally, a dual-tuned receive-only phased array was designed and built with the PIN diode circuit to switch between two resonance frequencies. A conventional dual-tuned birdcage coil was designed and built to transmit RF power. A unique feature of this coil is that the RF power is fed through two separate sets of four ports for more uniform 1H and 23Na excitation. We demonstrated that the performance is significantly improved at both frequencies with the PIN diode switched dual-frequency operation compared to an identical coil with a trap circuit.

Development of a new RF coil and gamma-ray radiation shielding assembly for improved MR image quality in SPECT/MRI.

Magnetic resonance (MR)-based multimodality imaging systems, such as single-photon emission tomography (SPECT)/magnetic resonance imaging (MRI) or positron emission tomography (PET)/MRI, face many difficulties because of problems with the compatibility of the nuclear detector system with the MR system. However, several studies have reported on the design considerations of MR-compatible nuclear detectors for combined SPECT/MRI. In this study, we developed a new radiofrequency (RF) coil and gamma-ray radiation shielding assembly to advance the practical implementation of SPECT/MRI in providing high sensitivity while minimizing the interference between the MRI and SPECT systems. The proposed assembly consists of a three-channel receive-only RF coil and gamma-ray radiation shields made of a specialized lead composite powder designed to reduce conductivity and thus minimizing any effect on the magnetic field arising from the induced eddy currents. A conventional birdcage RF coil was also tested for comparison with the proposed RF coil. Quality (Q)-factors were measured using both RF coils without any shielding, with solid lead shielding, and with our composite lead shielding. Signal-to-noise ratios (SNRs) were calculated using 4 T MR images of phantoms both with and without the new gamma-ray radiation shields. The Q-factor and SNR measurements demonstrate the improved MRI performance due to the new RF coil/gamma-ray radiation shield assembly designed for SPECT/MRI, making it a useful addition to multimodality imaging technology not only for animal studies but also for in vivo study of humans.

Development of an MR-compatible SPECT system (MRSPECT) for simultaneous data acquisition.

In medical imaging, single-photon emission computed tomography (SPECT) can provide specific functional information while magnetic resonance imaging (MRI) can provide high spatial resolution anatomical information as well as complementary functional information. In this study, we developed a miniaturized dual-modality SPECT/MRI (MRSPECT) system and demonstrated the feasibility of simultaneous SPECT and MRI data acquisition, with the possibility of whole-body MRSPECT systems through suitable scaling of components. For our MRSPECT system, a cadmium-zinc-telluride (CZT) nuclear radiation detector was interfaced with a specialized radiofrequency (RF) coil and placed within a whole-body 4 T MRI system. Various phantom experiments characterized the interaction between the SPECT and MRI hardware components. The metallic components of the SPECT hardware altered the B(0) field and generated a non-uniform reduction in the signal-to-noise ratio (SNR) of the MR images. The presence of a magnetic field generated a position shift and resolution loss in the nuclear projection data. Various techniques were proposed to compensate for these adverse effects. Overall, our results demonstrate that accurate, simultaneous SPECT and MRI data acquisition is feasible, justifying the further development of MRSPECT for either small-animal imaging or whole-body human systems by using appropriate components.

Initial Investigation of preclinical integrated SPECT and MR imaging.

Single-photon emission computed tomography (SPECT) can provide specific functional information while magnetic resonance imaging (MRI) can provide high-spatial resolution anatomical information as well as complementary functional information. In this study, we utilized a dual modality SPECT/MRI (MRSPECT) system to investigate the integration of SPECT and MRI for improved image accuracy. The MRSPECT system consisted of a cadmium-zinc-telluride (CZT) nuclear radiation detector interfaced with a specialized radiofrequency (RF) coil that was placed within a whole-body 4 T MRI system. The importance of proper corrections for non-uniform detector sensitivity and Lorentz force effects was demonstrated. MRI data were utilized for attenuation correction (AC) of the nuclear projection data and optimized Wiener filtering of the SPECT reconstruction for improved image accuracy. Finally, simultaneous dual-imaging of a nude mouse was performed to demonstrated the utility of co-registration for accurate localization of a radioactive source.

MREIT with SENSE acceleration using a dedicated RF coil design.

We have adapted a SENSE-accelerated imaging technique to magnetic resonance electrical impedance tomography (MREIT) in order to acquire data faster or improve spatial resolution without increasing the data acquisition time. We also designed and optimized an eight-channel, dedicated phased array coil for this application. The RF coil was designed as two planar arrays so that the open sides could accommodate the MREIT electrodes. A quasi-intrinsic decoupling scheme was used to minimize couplings between coil elements, and a restricted geometry optimization was applied to achieve high and uniform SNR within a given coil geometry and animal size. The impact of variability in the size of animals was also investigated in the optimization. This coil geometry provided approximately three times higher SNR at the center of a phantom when compared to a transmit/receive birdcage coil designed for MREIT of small animals. Therefore, the SNR was superior to the data acquired with volume coils even with three times SENSE acceleration. Both magnitude images and MREIT data were acquired from phantoms with and without SENSE acceleration, and the results were compared. The phantom studies demonstrated that conductivity maps can be reconstructed from MREIT data acquired with three times SENSE acceleration and that no discernible artifacts were observed when accelerated data acquisition was compared to non-accelerated data.

Cognitive dysfunction after experimental febrile seizures.

While the majority of children with febrile seizures have an excellent prognosis, a small percentage are later discovered to have cognitive impairment. Whether the febrile seizures produce the cognitive deficits or the febrile seizures are a marker or the result of underlying brain pathology is not clear from the clinical literature. We evaluated hippocampal and prefrontal cortex function in adult rats with a prior history of experimental febrile seizures as rat pups. All of the rat pups had MRI brain scans following the seizures. Rats subjected to experimental febrile seizures were found to have moderate deficits in working and reference memory and strategy shifting in the Morris water maze test. A possible basis for these hippocampal deficits involved abnormal firing rate and poor stability of hippocampal CA1 place cells, neurons involved in encoding and retrieval of spatial information. Additional derangements of interneuron firing in the CA1 hippocampal circuit suggested a complex network dysfunction in the rats. MRI T2 values in the hippocampus were significantly elevated in 50% of seizure-experiencing rats. Learning and memory functions of these T2-positive rats were significantly worse than those of T2-negative cohorts and of controls. We conclude that cognitive dysfunction involving the hippocampus and prefrontal cortex networks occur following experimental febrile seizures and that the MRI provides a potential biomarker for hippocampal deficits in a model of prolonged human febrile seizures.

The immune response to herpes simplex virus type 1 infection in susceptible mice is a major cause of central nervous system pathology resulting in fatal encephalitis.

This study was undertaken to investigate possible immune mechanisms in fatal herpes simplex virus type 1 (HSV-1) encephalitis (HSE) after HSV-1 corneal inoculation. Susceptible 129S6 (129) but not resistant C57BL/6 (B6) mice developed intense focal inflammatory brain stem lesions of primarily F4/80(+) macrophages and Gr-1(+) neutrophils detectable by magnetic resonance imaging as early as day 6 postinfection (p.i.). Depletion of macrophages and neutrophils significantly enhanced the survival of infected 129 mice. Immunodeficient B6 (IL-7R(-/-) Kit(w41/w41)) mice lacking adaptive cells (B6-E mice) and transplanted with 129 bone marrow showed significantly accelerated fatal HSE compared to B6-E mice transplanted with B6 marrow or control nontransplanted B6-E mice. In contrast, there was no difference in ocular viral shedding in B6-E mice transplanted with 129 or B6 bone marrow. Acyclovir treatment of 129 mice beginning on day 4 p.i. (24 h after HSV-1 first reaches the brain stem) reduced nervous system viral titers to undetectable levels but did not alter brain stem inflammation or mortality. We conclude that fatal HSE in 129 mice results from widespread damage in the brain stem caused by destructive inflammatory responses initiated early in infection by massive infiltration of innate cells.

Fast imaging for magnetic resonance electrical impedance tomography.

In magnetic resonance electrical impedance tomography (MREIT), currents are injected into an object, the resulting magnetic flux density is measured using MRI, and the conductivity distribution reconstructed using these MRI data. The relatively long acquisition times of conventional MREIT methods limit the signal averaging rate and are susceptible to motion artifacts. In this study, we reconstructed the conductivity distribution of an agarose gel phantom from data acquired in under a minute using a single-shot, spin echo, echo planar imaging (SS-SEPI) pulse sequence. The results demonstrate that SS-SEPI can be used for MREIT data acquisition.

In vivo MRI volumetric measurement of prostate regression and growth in mice.

BACKGROUND: Mouse models for treatment of late-stage prostate cancer are valuable tools, but assessing the extent of growth of the prostate and particularly its regression due to therapeutic intervention or castration is difficult due to the location, small size and interdigitated anatomy of the prostate gland in situ. Temporal monitoring of mouse prostate regression requires multiple animals and examination of histological sections. METHODS: Initially, T2-weighted magnetic resonance imaging (MRI) was performed on normal year-old C57/BL6 mice. Individual mice were repeatedly imaged using inhalation anesthesia to establish the reproducibility of the method and to follow hormone manipulation of the prostate volume. Subsequently, MRI fat signal was suppressed using a chemical shift-selective (CHESS) pulse to avoid signal contamination and enhance discrimination of the prostate. RESULTS: High field (7T) MRI provides high resolution (117 x 117 microm in plane), highly reproducible images of the normal mouse prostate. Despite long imaging times, animals can be imaged repeatedly to establish reliability of volume measurements. Prostate volume declines following castration and subsequently returns to normal with androgen administration in the same animal. CHESS imaging allowed discrimination of both the margins of the prostate and the dorsal-lateral lobes of the prostate (DLP) from the ventral lobes (VP). Castration results in a 40% reduction in the volume of the DLP and a 75% reduction in the volume of the VP. CONCLUSION: MRI assessment of the volume of the mouse prostate is precise and reproducible. MRI improves volumetric determination of the extent of regression and monitoring of the same mouse over time during the course of treatment is possible. Since assessing groups of animals at each time point is avoided, this improves the accuracy of the measurement of any manipulation effect and reduces the number of animals required.

Behavioral, histological, and ex vivo magnetic resonance imaging assessment of graded contusion spinal cord injury in mice.

This study characterized the Infinite Horizon (IH) Impactor for use in mouse models of contusion spinal cord injury (SCI), and investigated the feasibility and reliability of using magnetic resonance imaging (MRI) as a method to accurately measure lesion volume after mouse contusion SCI. Eight-week-old female C57Bl/6 mice received a mild (30 kilodyne), moderate (50 kilodyne), or severe (70 kilodyne) contusion injury at the T9 vertebral level. Uninjured control mice received a T9 laminectomy only. Functional recovery was assessed using the Basso, Beattie, Bresnahan (BBB) and Basso Mouse Scale (BMS) open-field locomotor rating scales. Next, 4% paraformaldehyde-perfused spinal cords were collected between the T6 and T12 spinal roots, and stored in phosphate-buffered saline (PBS) at 4 degrees C until MRI analysis. MRI lesion volumes were determined using T1-weighted images on a 7-Tesla MRI. Histology was performed on 20-microm polyester wax-embedded sections processed from the same spinal cords for stereological determination of fibronectin lesion volume and myelin basic protein spared white matter volume. Area of spared white matter at the epicenter was also analyzed. The results demonstrated that the IH Impactor produced precise, graded contusion SCI in mice. Lesion volumes were positively correlated with force of impact, and negatively correlated with spared white matter and functional recovery. Additionally, similar lesion volumes were detected using fibronectin staining and MRI analysis, although MRI may be more sensitive for milder injuries. These results give researchers more options in how to analyze spinal cord injuries in animal models.

Contrast and spatial resolution in MREIT using low amplitude current.

Magnetic resonance-electrical impedance tomography employs low amplitude currents injected or induced inside an object. The additional magnetic field due to these currents results in a phase in the MR images. In this study, a modified fast spin-echo sequence was used to measure this magnetic field, which is obtained by scaling the MR phase image. A finite element method with first order triangular elements was used for the solution of the forward problem. An iterated sensitivity matrix-based algorithm was developed for the inverse problem. The resulting ill-conditioned matrix equation was regularized using the Tikhonov method and solved using a conjugate gradient solver. The spatial and contrast resolution of the technique was tested using agarose gel phantoms. A circular phantom with 7 cm diameter and 1 cm thickness is used in the phantom experiments. The amplitude of the injected current was 1 mA. 3, 5 and 8 mm diameter insulators and high conductor objects are used for the spatial resolution study and an average full-width half-maximum value of 4.7 mm is achieved for the 3 mm insulator case. For the contrast analysis, the conductivity of a 15 mm object is varied between 44% and 500% with respect to the background and results are compared to the ideal reconstruction.

In vivo MRI electrical impedance tomography (MREIT) of tumors.

A significant increase in electrical conductivity of neoplasticities compared to healthy tissues and benign formations has been reported in several studies. We previously reported preliminary results with MR based Electrical Impedance Tomography (MREIT) on several phantoms and a single animal. In the presented study, we applied the technique on ten tumor-bearing rats and collected MREIT images to investigate the potential of MREIT for characterizing malignant tumors. Results show that the tumors had significantly higher mean conductivity compared to the mean of conductivity in the rest of the body. Although heterogeneity of conductivity was observed in the tumor, the mean was still higher than the background.

Measurement of ion diffusion using magnetic resonance electrical impedance tomography.

In magnetic resonance electrical impedance tomography (MREIT), currents are applied to an object, the resulting magnetic flux density measured using MRI and the conductivity distribution reconstructed using these MRI data. In this study, we assess the ability of MREIT to monitor changes in the conductivity distribution of an agarose gel phantom, using injected current pulses of 900 microA. The phantom initially contained a distinct region of high sodium chloride concentration which diffused into the background over time. MREIT data were collected over a 12 h span, and conductivity images were reconstructed using the iterative sensitivity matrix method with Tikhonov regularization. The results indicate that MREIT was able to monitor the changing conductivity and concentration distributions resulting from the diffusion of ions within the agarose gel phantom.